Novel propane-1,3-diol derivatives and use

ABSTRACT

A derivative of 2-methylenepropane-1,3-diol of the general formula I ##STR1## where O--A 1  and O--A 2 , which can be the same or different, each represents O, O--C(O), O--C(O)NH, O--C(S)NH or O--C(O)O, R 1  represents an alkyl or alkenyl group of 10-22 carbon atoms, n is an integer from 1 to 11, B +  represents a quaternary ammonium group, either N +  R 4  R 5  R 6 , or N +  (Het), where R 4 , R 5  and R 6  are similar or different alkyl groups of 1-4 carbon atoms, or two or all of R 4 , R 5  and R 6  may be incorporated into a cyclic or bicyclic structure, which may contain additional hetero atoms; X -  means the anion of a pharmceutically acceptable inorganic or organic acid; and R 2  and R 3  are the same or different, and represent hydrogen or alkl groups of 1-4 carbon atoms. 
     The present compounds have been shown to possess a PAF antagonistic effect and an inhibitory effect on the growth of tumor cells, and are thus valuable in the human and veterinary practice as platelet aggregation inhibitors, anti-thrombotic agents, anti-asthmatic agents, anti-allergic agents, anti-inflammatory agents, anti-hypotensive agents, anti-ulcer agents, anti-psoriatic agents, anti-graft rejection agents, anti-conception agents and anti-tumor agents.

The present invention relates to hitherto unknown derivatives of2-methylenepropane-1,3-diol, to methods for producing said newderivatives, to pharmaceutical compositions containing said newderivatives, to dosage units of said compositions, and to methods fortreating patients using said new derivatives.

Recently, a lipid chemical mediator which plays an important role inplatelet aggregation and in allergic, asthmatic, inflammatory andhypotensive reactions, was identified. It was named platelet activatingfactor (PAF), and it turned out to be a mixture of twoalkylphospholipids: ##STR2##

Compounds having PAF antagonistic effect (inhibitory effect on PAFactivity) are potentially useful as platelet agregation inhibitors,anti-thrombotic, anti-allergic, anti-asthmatic, anti-inflammatory,anti-hypotensive, anti-ulcer, anti-psoriatic, anti-graft rejectionand/or anti-conception agents (cf. D. J. Hanahan, Ann. Rev. Biochem.,55, (1986), 483-509. Abstracts from "Second International Conference onPlatelet-Activating Factor and Structurally Related Alkyl Ether Lipids",Gatlinburg, Tenn., U.S.A., Oct. 26-29, 1986).

Thus, investigations have been carried out in order to discovercompounds similar to PAF in their chemical structure and possessing aPAF antagonistic effect or having a hypotensive effect like PAF. Theresults of such investigations have been described e.g. in EuropeanPatent Publications Nos. 94586, 109255, 142333, 147768 and 157609 and inGerman patent application No. 3,307,925. All compounds described inthese applications are 1,2,3-trisubstituted propanes with three sp³-hybridized carbon atoms (like PAF): ##STR3##

Surprisingly, we have now discovered that the desired PAF antagonisticeffect can be obtained with derivatives of 2-methylenepropane-1,3-diolof the general formula I ##STR4## where O--A¹ and O--A², which can bethe same or different, each represents O, O--C(O), O--C(O)NH, O--C(S)NHor O--C(O)O, R¹ represents an alkyl or alkenyl group of 10-22 carbonatoms, n is an integer from 1 to 11, B⁺ represents a quaternary ammoniumgroup, either N⁺ R⁴ R⁵ R⁶, or N⁺ (Het), where R⁴, R⁵ and R⁶ are similaror different alkyl groups of 1-4 carbon atoms, or two or all of R⁴, R⁵and R⁶ may be incorporated into a cyclic or bicyclic structure, whichmay contain additional hetero atoms, such as 1-azetidinyl,1-pyrrolidinyl, 1-piperidinyl, 1-hexamethyleneiminyl, 1-imidazolidinyl,1-piperazinyl, 1-pyrrolyl, 1-imidazolyl, 4-morpholinyl,triethylenediamin-1-io, 1-quinuclidinio, and where --N⁺ (Het) representsan aromatic heterocyclic ring substituent containing at least onenitrogen atom, such as 1-pyridinio, 1-pyridazinio, 1-pyrimidinio,1-pyrazinio, 3-oxazolio, 3-thiazolio, 1-isoquinolinio, 1-quinolinio,3-alkyl-1-imidazolio, which may be substituted or unsubstituted; X⁻means the anion of a pharmaceutically acceptable inorganic or organicacid, e.g. the anion of an inorganic acid such as hydrochloric acid,hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid,nitric acid, or the anion of an organic acid such as acetic acid, lacticacid, tartaric acid, benzoic acid, citric acid, methanesulfonic acid,ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid,isethionic acid, in particular a halogen ion, i.e. chlorine, bromine,iodine ions, or the anions of methanesulfonic acid or p-toluenesulfonicacid; and R² and R³ are the same or different, and represent hydrogen oralkyl groups of 1-4 carbon atoms.

Preliminary tests seem to indicate that compounds of formula I, in whichR² =R³ =hydrogen, and n is an integer from 4 to 9, have particularlyinteresting properties.

The expression of an alkyl group or an alkenyl group in the definitionof the various symbols in this present specification including claimsrepresents a straight- or branched-chain alkyl or alkenyl group.

Examples of an alkyl group of 10 to 22 carbon atoms represented by R¹ inthe formula I are decyl, undecyl, dodecyl, tridecyl, tetradecyl,pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl,heneicosyl and docosyl group and isomers thereof; an alkyl group of 13to 19 carbon atoms is preferred.

Examples of an alkenyl group of 10 to 22 carbon atoms, represented by R¹in the formula I, when A¹ represents a single bond, are the groups whichhave a double bond between two carbon atoms in the alkyl groupenumerated above and when A¹ is different from a single bond, are thegroups which have a double bond between two carbon atoms except thecarbon atom adjacent to A¹ in the alkyl group enumerated above.

The present compounds have been shown to possess a PAF antagonisticeffect and an inhibitory effect on the growth of tumor cells, and arethus valuable in the human and veterinary practice as plateletaggregation inhibitors, anti-thrombotic agents, anti-asthmatic agents,anti-allergic agents, anti-inflammatory agents, anti-hypotensive agents,anti-ulcer agents, anti-psoriatic agents, anti-graft rejection agents,anti-conception agents and anti-tumor agents.

Some of the above effects have been confirmed in animal experimentsusing standard laboratory tests. Thus, the platelet activating factorantagonistic activity was tested by determination of inhibition ofPAF-induced

(1) platelet aggregation in platelet rich plasma from rabbits,

(2) bronchoconstriction in guinea pigs and

(3) acute hypotensive activity in rats

(1) Platelet rich plasma derived from rabbit blood was stabilized by 90mM trisodium citrate in an amount of one tenth of the blood volume. Theplatelet aggregation was carried out at 37° C. in an aggregometer. Aftera stabilizing period of 2 minutes, the compounds to be tested were added2 minutes before adding PAF to a final concentration of 30 ng/ml. TheEC₅₀ values represent the molar concentration of test compoundsinhibiting aggregation by 50%. Some of the tested compounds exhibitedEC₅₀ values <5×10⁻⁷ M.

(2) The tested compounds were able in doses of 1-20 mg/kg i.v. toinhibit bronchoconstriction in anaesthetized guinea pigs caused byintravenous injection of PAF (100 ng/kg body weight). The β-adrenergicreceptors of the animals were blocked during the experiment byintravenous injections of propranolol (0.1 mg/kg) on animals,muscle-depolarized by suxamethonum (NFN) (1.2 mg/kg i.v.). Thebronchoconstriction was measured ad modum Konzett-Rossler. (H. Konzettand R. Rossler, Arch. Exp. Pathol. Pharmacol., 195, (1940), 71-74).Respiration pressure was 8 cm H₂ O.

(3) Pretreatment of pentobarbital anaesthetized rats with the testedcompounds in doses of 0.1-20 mg/kg i.v. were able to inhibit hypotensiveblood pressure reactions induced by PAF i.v. (500 ng/kg body weight).The blood pressure was measured by transducers cannulated to arteriacarotis.

The present invention relates also to methods for producing thecompounds of formula I. They can be produced by reacting a compoundhaving the general formula II ##STR5## where A¹, A², R¹, R², R³ and nare as defined above and Z is a suitable leaving group, such aschloride, bromide, iodide, benzenesulfonate, toluenesulfonate ormethanesulfonate, with a trialkylamine NR⁴ R⁵ R⁶, where R⁴, R⁵ and R⁶are as defined above, or with a heterocyclic amine N(Het), as definedabove, alone or dissolved in a suitable solvent, such as methanol,ethanol, propanol, ethylacetate, methylene chloride, chloroform, etheror tetrahydrofuran or mixtures thereof. When Z⁻ is a halide, thereaction may be carried out in the presence of a silver salt, AgX, whereX⁻ is different from a halide. Any anion Z⁻ may be exchanged withanother anion X⁻ by known methods, such as ion exchange chromatography.

The starting material of formula II, where A² is a single bond, can beproduced from a compound of the formula III ##STR6## in which A¹, R¹,R², and R³ have the above meanings, by deprotonation with a strong base,such as sodium hydride or potassium t-butoxide in a suitable solvent,such as dimethylformamide, dioxane, 1,2-dimethoxyethane ortetrahydrofuran, followed by a reaction with Y(CH₂)_(n) Z, where Z and nhave the above meanings and Y is another suitable leaving group, such aschloride, bromide, iodide, benzenesulfonate, toluenesulfonate ormethanesulfonate, Y being more reactive than Z or equal to Z.

The starting material of formula II, where A² is a carbonyl group, canbe produced from a compound III by reaction with either

(a) HOOC(CH₂)_(n) Z and dicyclohexylcarbodiimide or

(b) ClC(O)(CH₂)_(n) Z,

in which Z and n have the above meanings, both in the presence of atertiary amine, such as triethylamine, pyridine or4-dimethylaminopyridine, alone or in an inert solvent, such as ether,methylene chloride or chloroform.

The starting material of the formula II, where A² is C(O)NH or C(S)NH,can be produced from a compound of formula III by reaction withOCN(CH₂)_(n) Z or SCN(CH₂)_(n) Z, respectively, n and Z having the abovemeanings, in the presence of a tertiary amine, such as triethylamine,pyridine or 4-dimethylaminopyridine, alone or in an inert solvent, suchas ether, methylene chloride, chloroform or toluene.

The starting material of the formula II, where A² is C(O)O, can beproduced from a compound of formula III by reaction withClC(O)O(CH₂)_(n) Z, n and Z having the above meanings, in the presenceof a tertiary amine, such as triethylamine, pyridine or4-dimethylaminopyridine, alone or in an inert solvent, such as ether,methylene chloride, chloroform or toluene.

The compounds of the formula III, where A¹ is a single bond, can beproduced from a compound of formula IV ##STR7## by deprotonation with astrong base, such as sodium hydride or potassium t-butoxide, in asuitable solvent, such as dimethylformamide, dioxane,1,2-dimethoxyethane or tetrahydrofuran, followed by reaction with R¹ Y,where R¹ and Y are as defined above.

The compounds of the formula III, where A¹ is a carbonyl group, can beproduced from a compound of formula IV by reaction with either

(a) HOOCR¹ and dicyclohexylcarbodiimide or

(b) ClC(O)R¹,

R¹ having the above meanings, both in the presence of a tertiary amine,such as triethylamine, pyridine or 4-dimethylaminopyridine, alone or inan inert solvent, such as ether, methylene chloride or chloroform.

The compounds of the formula III, where A¹ is C(O)NH or C(S)NH, can beproduced from a compound of formula IV by reaction with OCNR¹ or SCNR¹,respectively, R¹ having the above meanings, in the presence of atertiary amine, such as triethylamine, pyridine or4-dimethylaminopyridine, alone or in an inert solvent, such as ether,methylene chloride, chloroform or toluene.

The compounds of the formula III, where A² is C(O)O, can be producedfrom a compound of formula IV by reaction with ClC(O)R¹, R¹ having theabove meanings, in the presence of a tertiary amine, such astriethylamine, pyridine or 4-dimethylaminopyridine, alone or in an inertsolvent, such as ether, methylene chloride, chloroform or toluene.

The starting material of formula II, where A² is a single bond, can alsobe produced from a compound of the formula V ##STR8## in which A¹, R¹,R², R³, and n have the above meanings, by reaction with a sulfonic acidchloride, such as benzenesulfonyl chloride, toluenesulfonyl chloride ormethanesulfonyl chloride in the presence of a tertiary amine, such astriethylamine or pyridine, alone or in an inert solvent, such as ether,methylene chloride or chloroform.

The starting material of formula V can be produced from a compound ofthe formula VI ##STR9## in which A¹, R¹, R², R³ and n have the abovemeanings and G represents a suitable alcohol protecting group, such astriphenylmethyl, tetrahydropyranyl or methoxymethyl, by deprotectionwith a suitable deprotecting agent, such as toluenesulfonic acid,hydrogen chloride, sulfuric acid, acetic acid or acidic ion exchangeresin, in a suitable solvent, such as water, methanol or ethanol, aloneor mixed with an inert solvent, such as ether, chloroform or methylenechloride.

The compounds of the formula VI, where A¹ is a single bond, can beproduced from a compound of formula VII ##STR10## in which n and G havethe above meanings, by deprotection with a strong base, such as sodiumhydride or potassium t-butoxide, in a suitable solvent, such asdimethylformamide, dioxane, 1,2-dimethoxyethane or tetrahydrofuran,followed by reaction with R¹ Y, where R¹ and Y are as defined above.

The compounds of the formula VI, where A¹ is a carbonyl group, can beproduced from a compound of formula VII by reaction with either

(a) HOOCR¹ and dicyclohexylcarbodiimide or

(b) ClC(O)R¹,

R¹ having the above meanings, both in the presence of a tertiary amine,such as triethylamine, pyridine or 4-dimethylaminopyridine, alone or inan inert solvent, such as ether, methylene chloride or chloroform.

The compounds of the formula VI, where A¹ is C(O)NH or C(S)NH, can beproduced from a compound of formula VII by reaction with OCNR¹ or SCNR¹,respectively, R¹ having the above meanings, in the presence of atertiary amine, such as triethylamine, pyridine or4-dimethylaminopyridine, alone or in an inert solvent, such as ether,methylene chloride, chloroform or toluene.

The compounds of the formula VI, where A¹ is C(O)O, can be produced froma compound of formula VII by reaction with ClC(O)R¹, R¹ having the abovemeanings, in the presence of a tertiary amine, such as triethylamine,pyridine or 4-dimethylaminopyridine, alone or in an inert solvent, suchas ether, methylene chloride, chloroform or toluene.

The starting material of formula VII can be produced from a compound offormula IV, by deprotonation with a strong base, such as sodium hydrideor potassium t-butoxide, in a suitable solvent, such asdimethylformamide, dioxane, 1,2-dimethoxyethane or tetrahydrofuran,followed by reaction with Y(CH₂)_(n) G, where Y, n, and G are as definedabove.

The preparation of compounds of the formula IV is described in thechemical literature. When R² and R³ are different, the final compoundsof formula I may be provided as mixtures of or, after a suitableseparation procedure, well-known in the art, as the pure double bond (Eand Z) isomers.

It is a further object of the present invention to providepharmaceutical compositions which are useful in the human and veterinarypractice, and which may be used for enteral, parenteral or topicaladministration.

With this object in view, the compositions of the invention contain asan active component at least one compound of the formula I, togetherwith solid or liquid pharmaceutical carriers and/or diluents.

Furthermore, the compositions may contain other therapeutically activecomponents, such as glucocorticoids, anti-histamines, anticholinergicagents, methyl xanthines, β-adrenergic agents, salicylates,indomethacin, flufenamate, naproxen, timegadine, gold salts,penicillamine, serum cholesterol-reducing agents, retinoids, zinc salts,and anti-neoplastic agents, which can be appropriately administeredtogether with the present compounds in the treatment of hypotension,cancer, psoriasis and other proliferative skin disorders, asthma,allergy, inflammatory conditions, endotoxin shock, angina pectoris andthrombosis.

In the said compositions, the proportion of therapeutically activematerial to carrier substance can usually vary between 1% and 95% byweight. The compositions can be worked up to various pharmaceuticalforms of presentation, such as tablets, pills, dragees, suppositories,capsules, sustained-release tablets, solutions, suspensions and the likecontaining the compounds of formula I as atoxic salts, as defined above,mixed with carriers and/or diluents.

Pharmaceutically acceptable, non-toxic, organic or inorganic, solid orliquid carriers and/or diluents can be used to make up compositionscontaining the present compounds. Gelatine, lactose, starch, magnesiumstearate, talc, vegetable and animal fats and oils, gum, polyalkyleneglycol, buffers or other known carriers, auxiliary agents and/ordiluents for medicaments are all suitable.

Formulations of the present invention suitable for oral administrationmay be in the form of discrete units as capsules, sachets, tablets orlozenges, each containing a predetermined amount of the activeingredient; in the form of a powder or granules; in the form of asolution or a suspension in an aqueous liquid or non-aqueous liquid; orin the form of an oil-in-water emulsion or a water-in-oil emulsion. Theactive ingredient may also be administered in the form of a bolus,electuary or paste.

A tablet may be made by compression or moulding the active ingredientoptionally with one or more accessory ingredient(s). Compressed tabletsmay be prepared by compressing, in a suitable machine, the activeingredient in a free-flowing form such as a powder or granules,optionally mixed with a binder, lubricant, inert diluent, surface activeor dispersing agent. Moulded tablets may be made by moulding, in asuitable machine, a mixture of the powdered active ingredient and asuitable carrier moistened with an inert liquid diluent.

Liquid compositions for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirscontaining inert diluents commonly used in the art, such as distilledwater or ethanol. Besides inert diluents such compositions may alsocomprise adjuvants such as wetting and suspending agents, andsweetening, flavouring, perfuming and preserving agents.

Formulations for rectal administration may be in the form of asuppository incorporating the active ingredient and a carrier such ascocoa butter, or in the form of an enema.

Formulations suitable for administration to the nose or buccal cavityinclude powder, self-propelling and spray formulations such as aerosolsand atomizers. The formulations, when dispersed, preferably have aparticle size in the range of 10 to 100μ.

Such formulations are most preferably in the form of a finely comminutedpowder for pulmonary administration from a powder inhalation device orself-propelling powder-dispensing formulations, where the activeingredient, as a finely comminuted powder, may comprise even up to 99.9%w/w of the formulation. In the case of self-propelling solution andspray formulations, the effect may be achieved either by choice of avalve having the desired spray characteristics (i.e. being capable ofproducing a spray having the desired particle size) or by incorporatingthe active ingredient as a suspended powder in controlled particle size.These self-propelling formulations may be either powder-dispensingformulations or formulations dispensing the active ingredient asdroplets of a solution or suspension.

Self-propelling powder-dispensing formulations preferably comprisedispersed particles of solid active ingredients, and a liquid propellanthaving a boiling point below 18° C. at atmospheric pressure. The liquidpropellant may be any propellant known to be suitable for medicinaladministration and may comprise one or more lower alkyl hydrocarbons orhalogenated lower alkyl hydrocarbons or mixtures thereof; chlorinatedand fluorinated lower alkyl hydrocarbons are especially preferred.Generally, the propellant constitutes 50 to 99.9% w/w of the formulationwhilst the active ingredient constitutes 0.1 to 20% w/w, for exampleabout 2% w/w, of the formulation.

The pharmaceutically acceptable carrier in such self-propellingformulations may include other constituent in addition to thepropellant, in particular a surfactant or a solid diluent or both.Surfactants are desirable since they prevent agglomeration of theparticles of active ingredient and maintain the active ingredient insuspension. Especially valuable are liquid non-ionic surfactants andsolid anionic surfactants or mixtures thereof. Suitable liquid non-ionicsurfactants are esters and partial esters of fatty acids with aliphaticpolyhydric alcohols, for instance, sorbitan monooleate and sorbitantrioleate, known commercially as "Span 80" (Trade Name) and "Span 85"(Trade Name), respectively. The liquid non-ionic surfactants mayconstitute from 0.01 up to 20% w/w of the formulation, though preferablyit constitutes below 1% w/w of the formulation. Suitable solid anionicsurfactants include alkali metal, ammonium and amine salts of dialkylsulphosuccinate (where the alkyl groups have 4 to 12 carbon atoms). Thesolid anionic surfactants may constitute from 0.01 up to 20% w/w of theformulation, though preferably below 1% w/w of the composition. Soliddiluents may advantageously be incorporated in such self-propellingformulation where the density of the active ingredient differssubstantially from the density of the propellant; also, they help tomaintain the active ingredient in suspension. The solid diluent is inthe form of a fine powder, preferably having a particle size of the sameorder as that of the particles of the active ingredient. Suitable soliddiluents include sodium chloride, sodium sulphate and sugars.

Formulations of the present invention may also be in the form of aself-propelling formulation wherein the active ingredient is present insolution. Such self-propelling formulations may comprise the activeingredient, propellant and co-solvent, and advantageously ananti-oxidant stabilizer. The propellant is one or more of these alreadycited above. Co-solvents are chosen for their solubility in propellant,their ability to dissolve the active ingredient, and for their havingthe lowest boiling point consistent with these above-mentionedproperties. Suitable co-solvents are lower alkyl alcohols and ethers andmixtures thereof. The co-solvent may constitute 5 to 40% w/w of theformulation, though preferably less than 20% w/w of the formulation.Antioxidant stabilizers may be incorporated in suchsolutions-formulations to inhibit deterioration of the activeingredients and are conveniently alkali metal ascorbates or bisulphites.They are preferably present in an amount of up to 0.25% w/w of theformulation.

Such self-propelling formulations may be prepared by any method known inthe art. For example, the active ingredient (either as particles asdefined hereinbefore in suspension in a suitable liquid or in up to 20%w/v solution in an acceptable co-solvent, as appropriate) is mixed withany other constituents of a pharmaceutically acceptable carrier. Theresulting mixture is cooled, introduced in a suitable cooled containerand propellant is added thereto in liquid form; and the container issealed. Alternatively, such self-propelling formulations may be preparedby mixing the active ingredient either in particles as hereinbeforedefined or in 2 to 20% w/v alcohol or aqueous solution as appropriate,together with the remaining constituents of the pharmaceuticallyacceptable carrier other than the propellant; introducing the resultingmixture, optionally with some propellant, into a suitable container; andinjecting the propellant, under pressure, into the container at ambienttemperature through a valve which comprises a part of the container andis used to control release of the formulation from it. Desirably, thecontainer is purged by removing air from it at a convenient stage in thepreparation of the self-propelling formulation.

A suitable container for a self-propelling formulation is one providedwith a manually-operable valve and constructed of aluminium, stainlesssteel or reinforced glass. The valve should, of course, be one havingthe desired spray characteristics of particle size as hereinbeforedefined. Advantageously, the valve is of the type which delivers a fixedamount of the formulation on the occasion of each operation of thevalve, for example, about 50 to 100 microliters of formulation in eachdelivery.

Formulations of the present invention may also be in the form of anaqueous or dilute alcoholic solution, optionally a sterile solution, ofthe active ingredient for use in a nebuliser or atomizer, wherein anaccelerated air stream is used to produce a fine mist consisting ofsmall droplets of the solution. A buffering agent and a surface activeagent may also be included in such a formulation which should alsocontain a preservative such as methylhydroxybenzoate.

Other formulations suitable for nasal administration include a finepowder having a particle size of 10 to 100 microns which is administeredin the manner in which snuff is taken, i.e. by rapid inhalation throughthe nasal passage from a container of the powder held close up to thenose.

In addition to the aforementioned ingredients, the formulations of thisinvention may include one or more additional ingredients such asdiluents, buffers, flavouring agents, binders, surface active agents,thickeners, lubricants, preservatives, e.g. methylhydroxybenzoate(including anti-oxidants), emulsifying agents and the like.

Preparations according to the present invention for parenteraladministration include sterile aqueous or non-aqueous solutions,suspensions or emulsions. Examples of aqueous solvents or suspendingmedia are distilled water for injection and physiological salt solution.Examples of non-aqueous solvents or suspending media are propyleneglycol, polyethylene glycol, vegetable oils such as olive oil, alcoholssuch as ethanol, and Polysorbate 80 (registered Trade Mark). Thesecompositions may also include adjuvants such as preserving, wetting,emulsifying and dispersing agents. They may be sterilized, for example,by filtration through a bacteria-retaining filter, by incorporation ofsterilizing agents in the compositions or by irradiation. They may alsobe manufactured in the form of sterile solid compositions which can bedissolved in sterile water or some other sterile injectable mediumimmediately before use.

Formulations suitable for intra-articular administration may be in theform of a sterile aqueous preparation of the active ingredient.Liposomal formulations or biodegradable polymer systems may also be usedto present the active ingredient for both intra-articular and ophthalmicadministration.

Formulations suitable for topical administration include liquid orsemi-liquid preparations such as liniments, lotions, applications;oil-in-water or water-in-oil emulsions such as creams, ointments orpastes; or solutions or suspensions such as drops. For example, forophthalmic administration, the active ingredient may be present in theform of aqueous eye drops as, for example, a 0.1-1.0% solution.

Another object of the invention resides in the selection of a dose ofthe compounds of the invention and a dosage unit of the compositions ofthe invention which dose and dosage unit can be administered so that thedesired activity is achieved without simultaneous secondary effects. Inthe human therapy, the present compounds are conveniently administered(to adults) in dosage units of the compositions. By the term "dosageunit" is meant a unitary, i.e. a single dose which is capable of beingadministered to a patient, and which may be readily handled and packed,remaining as a physically stable unit dose comprising either the activematerial as such or a mixture of it with solid or liquid pharmaceuticaldiluents, carriers, solvents and/or auxiliary agents.

The dose of the present compounds to be administered depends upon, forexample, age, body weight, symptoms, the desired therapeutic effect, theroute of administration, and the duration of the treatment.

In the human adult, the doses per person are generally between 1 mg and2 g, preferably between 20 and 500 mg by oral administration, andbetween 100 μg and 200 mg, preferably between 1 and 100 mg by parenteraladministration and can be administered up to several times per day, theamounts referring to the content of one or more of the presentcompounds.

As mentioned above, the doses to be used depend on various conditions.Therefore, there may be cases in which doses greater than the rangesspecified above, or lower than the ranges specified above, may be used.

In the form of dosage units, the present compounds may be administeredonce or more times a day at appropriate intervals, always depending,however, on the condition of the patient, and in accordance with theprescription made by the medical practitioner.

Thus a daily dose will preferably be an amount of from 0.005 to 5 g of acompound of formula I, which conveniently can be divided into severalsingle doses.

In the continuous therapy of patients suffering from chronic diseases,the tablets or capsules are the appropriate form of pharmaceuticalpreparation, if desired in the form of sustained-release formulations.

In the veterinary practice the above pharmaceutical compositions mayalso be used, preferably in the form of dosage units containing from 5mg up to 25 g of the compound of formula I.

Still another object of the invention is to provide a method of treatingpatients, the method comprising administering to adult patients in needof treatment an effective amount of a compound of formula I, preferably,in the form of the dosage unit aforesaid. The compounds of formula I aretypically administered in amounts of 0.1-100 mg/kg body weight of thepatient/day.

In the treatment of patients, the present compounds can be administeredeither alone or together with other therapeutically active compounds.Such combined treatment can be performed with formulations containingmore or all of the therapeutically active compounds, or these may beadministered in separate formulations, these being given simultaneouslyor with suitable intervals.

In the treatment of patients, the daily dose is administered either atone time, or in divided dosages, e.g. two, three, or four times a day.

In the following "Preparations" the methods for preparing new startingmaterials and intermediates are more specifically described, and thesePreparations are followed by Examples which are intended to illustratebut not to limit the invention.

In the preparations and examples described below the followingabbreviations are used:

TLC: Thin Layer Chromatography on silica gel 60. Compounds are detectedby spraying with 2M sulfuric acid and 10% phosphomolybdic acid inethanol followed by heating to 150° C.

IR: Infrared absorption spectrum (5% in chloroform).

NMR: Nuclear Magnetic Resonance spectrum measured at 100 MHz indeuterochloroform (CDCl₃) with tetramethylsilane (TMS) as internalreference (δ=0.00).

Ether: Diethyl ether.

PREPARATION 1 3-Hexadecyloxy-2-methylenepropan-1-ol

1-Bromohexadecane (61.1 g), diethylformamide (200 ml) and2-methylenepropane-1,3-diol (17.7 g) were mixed. Sodium hydridedispersion (55-60% in oil, 21.8 g) was added over 10 minutes, and themixture was then stirred at 55° C. for 1 hour. The reaction mixture wascooled to room temperature and carefully quenched with water (400 ml),extracted with ether (2×200 ml), and the ether extracts were washed withwater (200 ml), dried over anhydrous magnesium sulfate, filtered andevaporated to dryness in vacuo. The product was purified through acolumn of silica gel 60 (70-230 mesh, 30 g) eluting with ether/pentane1:3. Further purification was achieved by chromatography on WatersPrepLC®/System 500A using a prepPAK®-500/SILICA cartridge withether/pentane 1:4 followed by ether as eluent.

Mp. 38°-40° C.

Elemental analysis: calculated C 76.86%, H 12.90%, found C 76.82%, H12.85%.

TLC (ether/pentane 1:1) R_(f) 0.4.

NMR: δ=0.9 (t, 3H), 1.0-1.8 (m, 28H), 2.21 (t, 1H), 3.42 (t, 2H), 4.03(s, 2H), 4.16 (d, 2H), 5.12 (m, 2H).

PREPARATION 2 3-Hexadecanoyloxy-2-methylenepropan-1-ol

2-Methylenepropane-1,3-diol (3.0 g) was dissolved in methylene chloride(40 ml). Dicyclohexylcarbodiimide (8.7 g), 4-dimethylaminopyridine (0.4g) and hexadecanoic acid (8.7 g) were added. The mixture was stirred for24 hours, filtered, and the filtrate was purified through a column ofsilica gel 60 (70-230 mesh, 30 g) eluting with ether/chloroform/pentane1:1:1. The eluate was washed with saturated sodium hydrogen carbonatesolution (3×70 ml), dried over anhydrous magnesium sulfate andevaporated to dryness in vacuo. Further purification was achieved bychromatography on a Waters PrepLC®/System 500A using aPrepPAK®-500/SILICA cartridge with ether/chloroform/pentane 1:1:3 aseluent.

NMR: δ=0.88 (t, 3H), 1.0-1.8 (m, 26H), 2.10 (t, 1H), 2.34 (t, 2H), 4.13(d, 2H), 4.64 (s, 2H), 5.20 (m, 2H).

PREPARATION 3 3-Octadecylaminocarbonyloxy-2-methylenepropan-1-ol

Octadecyl isocyanate (59.1 g) and 2-methylenepropane-1,3-diol (17.7 g)were dissolved and stirred in pyridine (100 ml) for 24 hours at 22° C.Water (200 ml) was added, and the mixture was extracted with chloroform(3×200 ml). The chloroform extracts were washed with water, dried overanhydrous magnesium sulfate, filtered and evaporated to dryness invacuo. The mixture was purified through a column of silica gel 60(70-230 mesh, 100 g) eluting with chloroform/ether 1:1. Furtherpurification was achieved by chromatography on a Waters PrepLC®/System500A using a PrepPAK®-500/SILICA cartridge with chloroform/ether/pentane1:1:3 as eluent. The product was recrystallized from acetone.

Mp. 71°-73° C.

Elemental analysis: calculated C 71.99%, H 11.82%, N 3.65%, found C71.93%, H 11.93%, N 3.64%.

TLC (chloroform/ether 1:1) R_(f) 0.5.

IR (CHCl₃): 3450, 2925, 2850, 1710, 1518 cm⁻¹.

NMR: δ=0.9 (t, 3H), 1.1-1.7 (m, 32H), 2.4 (t, 1H), 3.17 (m, 2H), 4.12(d, 2H), 4.64 (s, 2H), 4.75 (m, 1H), 5.17 (m, 2H).

PREPARATION 4 3-Pentadecylaminocarbonyloxy-2-methylenepropan-1-ol

Following the procedure described in Preparation 3, replacing octadecylisocyanate with pentadecyl isocyanate, the desired product was obtained.

Mp. 60°-62° C.

NMR: δ=0.88 (t, 3H), 1.0-1.7 (m, 26H), 2.63 (t, 1H), 3.16 (m, 2H), 4.11(d, 2H), 4.63 (s, 2H), 4.8 (m, 1H), 5.16 (m, 2H).

PREPARATION 5 3-Hexadecylaminothiocarbonyloxy-2-methylenepropan-1-ol

Hexadecyl isothiocyanate (9.65 g) and 2-methylenepropane-1,3-diol) (3.0g) were heated with pyridine (17 ml) and 4-dimethylaminopyridine (0.8 g)to 104° C. for 6.5 hours. The mixture was evaporated to dryness in vacuoand chromatographed on a Waters PrepLC®/System 500A using aPrepPAK®-500/SILICA cartridge with ether/chloroform/hexane 2:2:9 aseluent.

PREPARATION 6 3-Hexadecyloxycarbonyloxy-2-methylenepropan-1-ol

2-Methylenepropane-1,3-diol (5.0 g), hexadecyloxycarbonylchloride (17.4g) and pyridine (4.4 g) was dissolved in methylene chloride (60 ml). Themixture was stirred for 2.5 hours at 22° C. The mixture was purifiedthrough a column of silica gel 60 (70-230 mesh, 30 g), eluting withether/chloroform 1:1. Further purification was achieved bychromatography on a Waters PrepLC®-System 500A using aPrepPAK®-500-SILICA cartridge with ether/chloroform/pentane 1:1:3 aseluent.

NMR: δ=0.88 (t, 3H), 1.1-1.8 (m, 28H), 1.94 (bt, 1H), 4.14 (m, 4H), 4.68(bs, 2H), 5.24 (m, 2H).

PREPARATION 71-Hexadecyloxy-3-[4-(methanesulfonyloxy)butoxy]-2-methylenepropane

3-Hexadecyloxy-2-methylenepropan-1-ol (from Preparation 1) (5.0 g),sodium hydride dispersion (55-60% in oil, 1.55 g), and1,4-dimethanesulfonyloxybutane (12.5 g) were mixed in drydimethylformamide (25 ml) and stirred at 50° C. for 1 hour. The mixturewas cooled to room temperature and ether (100 ml) was added. The mixturewas carefully quenched with water (100 ml). The aqueous phase wasseparated and extracted with ether (100 ml). The combined ether extractswere washed with water (100 ml), dried over anhydrous magnesium sulfate,filtered and evaporated to dryness in vacuo. The product was purified bychromatography on silica gel 60 (70-230 mesh, 50 g) eluting withether/pentane 1:2.

Elemental analysis: calculated C 64.88%, H 10.89%, S 6.95%, found C64.86%, H 10.82%, S 6.76%.

TLC (ether/pentane 1:1) R_(f) 0.3.

NMR: δ=0.9 (t, 3H), 1.1-2.0 (m, 32H), 2.99 (s, 3H), 3.35 (m, 4H), 3.95(bs, 4H), 4.26 (t, 2H), 5.15 (bs, 2H).

PREPARATION 81-Hexadecyloxy-3-[5-(methanesulfonyloxy)pentyloxy]-2-methylenepropane

3-Hexadecyloxy-2-methylenepropan-1-ol (from Preparation 1) (4.45 g),sodium hydride dispersion (55-60% in oil, 1.4 g), and1,5-dimethanesulfonyloxypentane (10.9 g) were mixed in drydimethylformamide (33 ml) and stirred at 54° C. for 20 hours. Followingthe work-up procedure described in Preparation 7, the desired productwas obtained.

PREPARATION 91-Octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropane

3-Octadecylaminocarbonyloxy-2-methylenepropan-1-ol (from Preparation 3)(1.62 g), dicyclohexylcarbodiimide (1.08 g), 4-dimethylaminopyridine (52mg), and 6-bromohexanoic acid (0.91 g) were stirred in ether (50 ml) for20 hours at 22° C. Chloroform (50 ml) was added, and the mixture wasfiltered. The filtrate was purified through a column of silica gel 60(70-230 mesh, 40 g) eluting with chloroform/ether 1:1. Furtherpurification was achieved by chromatography on a Waters PrepLC®/System500A using a PrepPAK®-500/SILICA cartridge with chloroform/ether/pentane1:1:3 as eluent.

TLC (chloroform/ether/pentane 1:1:1) R_(f) 0.75.

NMR: δ=0.9 (t, 3H), 1.2-2.0 (m, 38H), 2.37 (t, 2H), 3.17 (m, 2H), 3.40(t, 2H), 4.60 (s, 4H), 4.7 (m, 1H), 5.24 (bs, 2H).

PREPARATION 101-Octadecylaminocarbonyloxy-3-(5-bromopentanoyloxy)-2-methylenepropane

Following the procedure described in Preparation 9, replacing6-bromohexanoic acid with 5-bromopentanoic acid, the desired product wasobtained.

NMR: δ=0.9 (t, 3H), 1.1-1.65 (m, 32H), 1.7-2.0 (m, 4H), 2.39 (t, 2H),3.17 (m, 2H), 3.41 (t, 2H), 4.60 (s, 4H), 4.7 (m, 1H), 5.24 (bs, 2H).

PREPARATION 111-Octadecylaminocarbonyloxy-3-(8-bromooctanoyloxy)-2-methylenepropane

Following the procedure described in Preparation 9, but replacing6-bromohexanoic acid with 8-bromooctanoic acid, the desired product wasobtained.

NMR: δ=0.88 (t, 3H), 1.0-2.0 (m, 42H), 2.34 (t, 2H), 3.16 (m, 2H), 3.40(t, 2H), 4.60 (bs, 4H), 4.65 (m, 1H), 5.24 (bs, 2H).

PREPARATION 121-Pentadecylaminocarbonyloxy-3-(6-bromohexanoyl)-2-methylenepropane

Following the procedure described in Preparation 9, but replacing3-octadecylaminocarbonyloxy-2-methylenepropan-1-ol with3-pentadecylaminocarbonyloxy-2-methylenepropan-1-ol (from Preparation4), the desired product was obtained.

NMR: δ=0.88 (t, 3H), 1.0-2.0 (m, 32H), 2.30 (t, 2H), 3.16 (m, 2H), 3.40(t, 2H), 4.60 (bs, 4H), 4.65 (m, 1H), 5.25 (bs, 2H).

PREPARATION 131-Pentadecylaminocarbonyloxy-3-(8-bromooctanoyloxy)-2-methylenepropane

Following the procedure described in Preparation 9, but replacing3-octadecylaminocarbonyloxy-2-methylenepropan-1-ol with3-pentadecylaminocarbonyloxy-2-methylenepropan-1-ol (from Preparation4), and replacing 6-bromohexanoic acid with 8-bromooctanoic acid, thedesired product was obtained.

NMR: δ=0.88 (t, 3H), 1.0-2.0 (m, 36H), 2.34 (t, 2H), 3.16 (m, 2H), 3.39(t, 2H), 4.59 (bs, 4H), 4.65 (m, 1H), 5.24 (bs, 2H).

PREPARATION 141-Octadecylaminocarbonyloxy-3-(4-bromobutylaminocarbonyloxy)-2-methylenepropane

3-Octadecylaminocarbonyloxy-2-methylenepropan-1-ol (from Preparation 3)(2.0 g) was dissolved in methylene chloride (40 ml).4-Dimethylaminopyridine (0.13 g) and 4-bromobutyl isocyanate (1.30 g)were added, and the mixture was stirred for 22 hours at 22° C. Ether (40ml) was added, and the mixture was purified through a column of silicagel 60 (70-230 mesh, 20 g) eluting with ether/chloroform 1:1. Furtherpurification was achieved by chromatography on a Waters PrepLC®/System500A using a PrepPAK®-500/SILICA cartridge with ether/chloroform/pentane1:1:2 as eluent.

NMR: δ=0.9 (t, 3H), 1.1-2.0 (m, 36H), 3.2 (m, 4H), 3.42 (t, 2H), 4.59(s, 4H), 5.22 (s, 2H).

PREPARATION 151-Octadecylaminocarbonyloxy-3-(2-bromoethylaminocarbonyloxy)-2-methylenepropane

Following the procedure described in Preparation 14, but replacing4-bromobutyl isocyanate with 2-bromoethyl isocyanate, the desiredproduct was obtained.

NMR: δ=0.9 (t, 3H), 1.1-1.6 (m, 32H), 3.16 (m, 2H), 3.3-3.7 (m, 4H),4.61 (s, 4H), 5.24 (s, 2H).

PREPARATION 161-Hexadecyloxy-3-(4-bromobutylaminocarbonyloxy)-2-methylenepropane

3-Hexadecyloxy-2-methylenepropane-1-ol (from Preparation 1) (2.0 g) wasdissolved in ether (40 ml). 4-Dimethylaminopyridine (0.16 g) and4-bromobutyl isocyanate (1.6 g) were added, and the mixture was stirredfor 22 hours at 22° C. Chloroform (40 ml) was added, and the mixture waspurified through a column of silica gel 60 (70-230 mesh, 20 g) elutingwith ether/chloroform 1:1. Further purification was achieved bychromatography on a Waters PrepLC®/System 500A using aprepPAK®-500/SILICA cartridge with ether/chloroform 1:1 as eluent.

NMR: δ=0.88 (t, 3H), 1.26 (bs, 26H), 1.3-2.0 (m, 6H), 3.21 (q, 2H), 3.35(t, 2H), 3.39 (t, 2H), 3.97 (bs, 2H), 4.58 (bs, 2H), 4.60 (bs, 1H), 5.18(bs, 2H).

PREPARATION 171-Hexadecyloxy-3-(2-bromoethylaminocarbonyloxy)-2-methylenepropane

Following the procedure described in Preparation 16, but replacing4-bromobutyl isocyanate with 2-bromoethyl isocyanate, the desiredproduct was obtained.

NMR: δ=0.88 (t, 3H), 1.26 (bs, 26H), 1.50 (m, 2H), 3.42 (q, 2H), 3.50(m, 4H), 3.97 (bs, 2H), 4.61 (bs, 2H), 5.00 (bs, 1H), 5.19 (bs, 2H).

PREPARATION 18 1-Hexadecyloxy-3-(6-bromohexanoyloxy)-2-methylenepropane

3-Hexadecyloxy-2-methylenepropan-1-ol (from Preparation 1) (1.8 g) wasdissolved in ether (35 ml). Dicyclohexylcarbodiimide (1.5 g),4-dimethylaminopyridine (0.07 g) and 6-bromohexanoic acid (1.2 g) wasadded, and the mixture was stirred at 22° C. for 18 hours. The reactionmixture was filtered, and the filtrate was washed with water (35 ml), 5%acetic acid in water (35 ml) and water (35 ml). The ether solution wasdried over anhydrous magnesium sulfate, filtered and evaporated invacuo. The crude product was purified by chromatography on a WatersPrepLC®/System 500A using a PrepPAK®-500/SILICA cartridge first withether/pentane 1:4 and in a second run with methylene chloride/hexane 1:4as eluent.

NMR: δ=0.9 (t, 3H), 1.1-2.0 (m, 34H), 2.36 (t, 2H), 3.40 (t, 4H), 3.97(bs, 2H), 4.60 (bs, 2H), 5.20 (m, 2H).

PREPARATION 19 1-Hexadecyloxy-3-bromoacetoxy-2-methylenepropane

Following the procedure described in Preparation 18, but replacing6-bromohexanoic acid with bromoacetic acid, the desired product wasobtained.

NMR: δ=0.9 (t, 3H), 1.1-2.0 (m, 28H), 3.40 (t, 2H) 3.85 (s, 2H), 3.98(bs, 2H), 4.70 (bs, 2H), 5.24 (bs, 2H).

PREPARATION 20 1-Hexadecyloxy-3-(4-bromobutanoyloxy)-2-methylenepropane

Following the procedure described in Preparation 18, but replacing6-bromohexanoic acid with 4-bromobutanoic acid, the desired product wasobtained.

PREPARATION 211-Hexadecyloxy-3-(11-bromoundecanoyloxy)-2-methylenepropane

Following the procedure described in Preparation 18, but replacing6-bromohexanoic acid with 11-bromoundecanoic acid, the desired productwas obtained.

NMR: δ=0.9 (t, 3H), 1-2 (m, 44H), 2.34 (t, 2H), 3.40 (t, 4H), 3.97 (bs,2H), 4.59 (bs, 2H), 5.20 (m, 2H).

PREPARATION 221-Hexadecanoyloxy-3-(6-bromohexanoyloxy)-2-methylenepropane

Following the procedure described in Preparation 9, but replacing3-octadecylaminocarbonyloxy-2-methylenepropan-1-ol with3-hexadecanoyloxy-2-methylenepropan-1-ol (from Preparation 2), thedesired product was obtained.

NMR: δ=0.88 (t, 3H), 1.1-2.0 (m, 32H), 2.3 (m, 4H), 3.40 (t, 2H), 4.60(bs, 4H), 5.26 (bs, 2H).

PREPARATION 231-Hexadecanoyloxy-3-(4-bromobutylaminocarbonyloxy)-2-methylenepropane

Following the procedure described in Preparation 14, but replacing3-octadecylaminocarbonyloxy-2-methylenepropan-1-ol with3-hexadecanoyloxy-2-methylenepropan-1-ol (from Preparation 2), thedesired product was obtained.

PREPARATION 241-Hexadecylaminothiocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropane

Following the procedure described in Preparation 9, but replacing3-octadecylaminocarbonyloxy-2-methylenepropan-1-ol with3-hexadecylaminothiocarbonyloxy-2-methylenepropan-1-ol (from Preparation5), the desired product was obtained.

NMR: δ=0.88 (t, 3H), 1.25 (s, 28H), 1.1-2.0 (m, 6H), 2.38 (t, 2H),3.1-3.5 (m, 4H), 4.62 (bs, 2H), 4.98 (m, 2H), 5.28 (bs, 2H), 6.2-6.8 (m,1H).

PREPARATION 251-Hexadecyloxycarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropane

Following the procedure described in Preparation 9, but replacing3-octadecylaminocarbonyloxy-2-methylenepropan-1-ol with3-hexadecyloxycarbonyloxy-2-methylenepropan-1-ol (from Preparation 6),the desired products was obtained.

NMR: δ=0.88 (s, 3H), 1.25 (s, 28H), 1.2-2.0 (m, 6H), 2.33 (t, 2H), 3.40(t, 2H), 4.13 (t, 2H), 4.63 (bs, 4H), 5.31 (s, 2H).

PREPARATION 26 3-Octadecylaminocarbonyloxy-2-isopropylidenepropan-1-ol

Following the procedure described in Preparation 3, but replacing2-methylenepropane-1,3-diol with 2-isopropylidenepropane-1,3-diol, thedesired product was obtained.

NMR: δ=0.88 (t, 3H), 1.26 (bs, 32 H), 1.81 (bs, 1H), 2.60 (bs, 1H), 3.14(q, 2H), 4.17 (s, 2H), 4.70 (s, 3H).

PREPARATION 271-Octadceylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-isopropylidenepropane

Following the procedure described in Preparation 9, but replacing3-octadecylaminocarbonyloxy-2-methylenepropan-1-ol with3-octadecylaminocarbonyloxy-2-isopropylidenepropan-1-ol (fromPreparation 26), the desired compound was obtained.

NMR: δ=0.86 (t, 3H), 1.26 (s, 32H), 1.1-1.9 (m, 6H), 1.82 (s, 3H), 1.84(s, 3H), 2.32 (t, 2H), 3.14 (q, 2H), 3.40 (t, 2H), 4.6 (bs, 1H), 4.68(bs, 4H).

PREPARATION 28 3-Octadecylaminocarbonyloxy-2-ethylidenepropan-1-ol

Following the procedure described in Preparation 3, but replacing2-metyylenepropane-1,3-diol with 2-ethylidenepropane-1,3-diol an approx.1:1 mixture of E- and Z-isomers of the desired compound is obtained.

PREPARATION 291-Octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-ethylidenepropane

Following the procedure described in Preparation 9, but replacing3-octadecylaminocarbonyloxy-2-methylenepropan-1-ol with an approx. 1:1mixture of E- and Z-isomers of3-octadceylaminocarbonyloxy-2-ethylidenepropan-1-ol (from Preparation28), an approx 1:1 mixture of E- and Z-isomers of the desired compoundis obtained.

PREPARATION 301-Hexadecanoyloxy-3-(8-bromooctanoyloxy)-2-methylenepropane

Following the procedure described in Preparation 9, but replacing3-octadecylaminocarbonyloxy-2-methylenepropan-1-ol with3-hexadecanoyloxy-2-methylenepropan-1-ol (from Preparation 2), andreplacing 6-bromohexanoic acid with 8-bromooctanoic acid, the desiredproduct was obtained.

NMR: δ=0.88 (s, 3H), 1.26 (s, 28H9, 1.2-1.9 (m, 8H), 2.34 (t, 4H), 3.39(t, 2H), 4.59 (s, 4H), 5.25 (s, 2H).

PREPARATION 311-Octadecylaminocarbonyloxy-3-(7-bromoheptanoyloxy)-2-methylenepropane

Following the procedure described in Preparation 9, but replacing6-bromohexanoic acid with 7-bromoheptanoic acid, the desired product wasobtained.

M.p. 49° C. (from methanol).

Elemental analysis: calculated C 62.70%, H9.82%, N 2.445, found C62.83%, H 9,79%, N 2.56%.

NMR: δ=0.87 (t, 3H), 1,26 (s, 34H), 1.1-2.0 (m, 6H), 2.35 (t, 2H), 3.14(q, 2H), 3.40 (t, 2H), 4.60 (s, 4H), 4.65 (m, 1H), 5.24 (m, 2H).

PREPARATION 321-Octadecylaminocarbonyloxy-3-[7-(methanesulfonyloxy)heptanoxyloxy]-2-methylenepropane

Following the procedure described in Preparation 9, but replacing6-bromohexanoic acid with 7-(methanesulfonyloxy)heptanoic acid, thedesired product was obtained.

NMR: δ=0.88 (t, 3H), 1.25 (s, 32H), 1.0-1.8 (m, 8H), 2.32 (t, 2H), 2.99(s, 3H), 3.16 (q, 2H), 4.22 (t, 2H), 4.59 (s, 4H), 4.70 (m, 1H), 5.23(bs, 2H).

PREPARATION 331-Octadecylaminocarbonyloxy-3-[8-(1-imidazolyl)octanoyloxy]-2-methylenepropane

1-Octadecylaminocarbonyloxy-3-(8-bromooctanoyloxy)-2-methylenepropane(from Preparation 11) (1.18 g) and imidazole (0.68 g) were stirred intoluene (20 ml) at 104° C. for 14 hours. The mixture was cooled andevaporated in vacuo. The residue was chromatographed on silica gel 60(70-230 mesh, 40 g) with ether/chloroform/triethylamine (1:1:0.04) aseluent to give the desired product.

NMR: δ=0.87 (t, 3H), 1.25 (s, 36H), 1.2-1.8 (m, 6H), 2.33 (t, 2H), 3.16(q, 2H), 3.91 (t, 2H), 4.59 (4.95 (bt, 1H), 5.22 (s, 2H), 6.89 (s, 1H),7.04 (s, 1H), 7.40 (s, 1H).

PREPARATION 341-Octadecylaminocarbonyloxy-3-[6-(1-imidazolyl)hexanoyloxy]-2-methylenepropane

Following the procedure described in Preparation 33, but replacing1-octadecylaminocarbonyloxy-3-(8-bromooctanoyloxy)-2-methylenepropanewith1-octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropane(from Preparation 9), the desired product was obtained.

NMR: δ=0.88 (t, 3H), 1.25 (s, 32H), 1.0-2.0 (m, 6H), 2.34 (t, 2H), 4.16(q, 2H), 3.93 (t, 2H), 4.58 (s, 4H), 5.06 (m, 1H), 5.23 (s, 2H), 6.89(s, 1H), 7.03 (s, 1H), 7.45 (s, 1H).

PREPARATION 351-Octadeyclaminocarbonyloxy-3-(5-bromopentylaminocarbonyloxy)-2-methylenepropane

Following the procedure described in Preparation 14, but replacing4-bromobutyl isocyanate with 5-bromopentyl isocyanate, the desiredproducts was obtained.

NMR: δ=0.87 (t, 3H), 1.25 (s, 32H), 1.0-2.0 (m, 6H), 3.15 (m, 4H), 3.40(t, 2H), 4.59 (s, 4H), 4.65 (m, 2H), 5.22 (s, 2H).

PREPARATION 361-Octadecylaminocarbonyloxy-3-(7-bromohepthylaminocarbonyloxy)-2-methylenepropane

Following the procedure described in Preparation 14, but replacing4-bromobutyl isocyanate with 7-bromoheptyl isocyanate, the desiredproduct was obtained.

NMR: δ=0.88 (t, 3H, 1.26 (s, 32H), 1.0-2.0 (m, 10H), 3.16 (q, 4H), 3.40(t, 2H), 4.59 (s, 3h), 4.70 (bs, 2H), 5.22 (s, 2H).

PREPARATION 37 3-Octadecyloxycarbonyloxy-2-methylenepropan-1-ol

Following the procedure described in Preparation 6, but replacinghexadecyloxycarbonyl chloride with octadecyloxycarbonyl chloride, thedesired product was obtained.

NMR: δ=0.88 (t, 3H), 1.26 (s, 32H), 2.0 (ts, 1H), 4.13 (t, 2H), 4.16 (s,2H), 4.68 (s, 2H), 5.23 (m, 2H).

PREPARATION 381-Octadecyloxycarbonyloxy-3-(7-bromoheptanoyloxy)-2-methylenepropane

Following the procedure described in Preparation 9, but replacing3-octadecylaminocarbonyloxy-2-methylenepropan-1-ol with3-octadecyloxycarbonyloxy-2-methylenepropan-1-ol and 6-bromohexanoicacid with 7-bromoheptanoic acid, the desired product was obtained.

NMR: δ=0.88 (t, 3H), 1.26 (s, 32H), 1.2-2.0 (m, 8H), 2.35 (t, 2H), 3.40(t, 2H), 4.13 (t, 2H), 4.63 (s, 4H), 5.31 (s, 2H).

PREPARATION 391-Hexadecyloxycarbonyloxy-3-(8-bromooctanoyloxy)-2-methylenepropane

Following the procedure described in Preparation 9, but replacing3-octadecylaminocarbonyloxy-2-methylenepropan-1-ol with3-hexadceyloxycarbonyloxy-2-methylenepropan-1-ol and 6-bromohexanoicacid with 8-bromooctanoic acid, the desired product was obtained.

NMR: δ=0.88 (s, 3H), 1.25 (bs, 28H), 1.2-1.9 (m, 10H), 2.30 (t, 2H),3.40 (t, 2H), 4.13 (t, 2H), 4.64 (bs, 4H), 5.31 (m, 2H).

PREPARATION 401-octadecylaminocarbonyloxy-3-(8-bromooctanoyloxy)-2-isopropylidenepropane

Following the procedure described in Preparation 9, but replacing3-octadecylaminocarbonyloxy-2-methylenepropan-1-ol with3-octadecylaminocarbonyloxy-2-isopropylidenepropan-1-ol (fromPreparation 26) and 6-bromohexanoic acid with 8-bromooctanoic acid, thedesired product was obtained.

NMR: δ=0.88 (s, 3H), 1.25 (bs, 30H), 1.1-1.8 (m, 12H), 1.83 (s, 3H),1.85 (s, 3H), 2.30 (t, 2H), 3.14 (q, 2H), 3.39 (t, 2H), 4.55 (bs, 1H),4.67 (bs, 4H).

PREPARATION 41 3-Pentadecylaminocarbonyl-2-isopropylidenepropan-1-ol

Following the procedure described in Preparation 3, but replacingoctadecyl isocyanate with pentadecyl isocyanate and2-methylenepropane-1,3-diol with 2-isopropylidenepropan-1,3-diol, thedesired product was obtained.

NMR: δ=0.88 (t, 3H), 1.25 (bs, 26H), 1.81 (s, 6H), 2.65 (bs, 1H), 3.15(q, 2H), 4.17 (s, 2H), 4.70 (bs, 3H).

PREPARATION 421-Pentaceylaminocarbonyloxy-3-(8-bromooctanoyloxy)-2-isopropylidenepropane

Following the procedure described in Preparation 9, but replacing3-octadeyclaminocarbonyloxy-2-methylenepropan-1-ol with3-pentadecylaminocarbonyloxy-2-isopropylidenepropan-1-ol (fromPreparation 41) and 6-bromohexanoic acid with 8-bromooctanoic acid, thedesired products was obtained.

NMR: δ=0.88 (t, 3H), 1.25 (bs, 26H), 1.1-1.8 (m, 10H), 1.82 (s, 3H),1.84 (s, 3H), 2.30 (t, 2H), 3.10 (q, 2H), 3.39 (t, 2H), 4.60 (bs, 1H),4.66 (bs, 4H).

PREPARATION 431-Pentadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-isopropylidenepropane

Following the procedure described in Preparation 9, but replacing3-octadecylaminocarbonyloxy-2-methylenepropan-1-ol with3-pentadecylaminocarbonyloxy-2-isopropylidenepropan-1-ol (fromPreparation 41), the desired product was obtained.

NMR: δ=0.88 (t, 3H), 1.25 (bs, 26H), 1.1-1.9 (m, 6H), 1.82 (s, 3H), 1.84(s, 3H), 2.32 (t, 2H), 3.14 (q, 2H), 3.40 (t, 2H), 4.67 (bs, 5H).

PREPARATION 44 3-(6-Bromohexanoyloxy)-2-methylenepropan-1-ol

2-Methyllenepropane-1,3-diol (5.0 g), 6-bromohexaoic acid (11.1 g),4-dimethylaminopyridine 0.7 g) and dicyclohexylcarbodiimide (14.5 g)were mixed in methylene chloride (60 ml). After stirring for 4 hours at22° C. ether was added, the mixture was filtered, and the filtrate waspurified through a column of silica gel 60 (70-230 mesh, 30 g), elutingwith ether/chloroform 1:1. Further purification was achieved bychromatography on Waters PrepLC®/System 500A using a prepPAK®-500/SILICA cartridge with ether/chloroform/pentane 1:1:3 as eluent.

NMR: δ=1.3-2.0 (m, 6H), 2.33 (m, 3H), 3.41 (t, 2H), 4.13 (d, 2H), 4.65(s, 2H), 5.20 (m, 2H).

PREPARATION 451-Tridecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropane

3-(6-Bromohexanoyloxy)-2-methylenepropan-1-ol (from Preparation 44)(0.58 g), tridecyl isocyanate (0.55 g) and 4-dimethylaminopyridine (0.05g) were mixed in methylene chloride (3 ml). After stirring for 23 hoursat 22° C. the mixture was filtered, and the filtrate was purifiedthrough a column of silica gel 60 (70-230 mesh, 4 g) eluting withether/chloroform 1:1. Further purification was achieved bychromatography on Waters PrepLC®/System 500A using a prepPAK®-500/SILICAcartridge with ether/chloroform/pentane 1:1:4 as eluent.

NMR: δ=0.88 (s, 3H), 1.25 (s, 22H), 1.1-2.0 (m, 6H), 2.37 (t, 2H), 3.16(q, 2H), 3.40 (t, 2H), 4.60 (s, 4H), 4.70 (bs, 1H), 5.25 (bs, 2H).

PREPARATION 46 3-[6-(Triphenylmethoxy)hexyloxy]-2-methylenepropan-1-ol

Sodium hydride (from 55-60% oil dispersion (0.52 g) washed with pentane(3×3 ml)), dry dimethylformamide (20 ml), and2-metyylenepropane-1,3-diol (1.0 g) were mixed. After 1 hour when H₂-evolution had ceased 1-chloro-6-(triphenylmethoxy)hexane (4.2 g) wasadded, and the mixture was stirred for 3 hours at 85° C. After coolingwater (20 ml) was carefully added, and the mixture was extracted withether (2×100 ml). The ether extracts were washed with water (100 ml),dried over magnesium sulfate and evaporated to dryness in vacuo. Theproduct was purified through a column of silica gel 60 (70-230 mesh, 40g) eluting with ether. Futher purification was achieved bychromatography on Waters PrepLC®/System 500A using a prepPAK®-500/SILICAcartridge with ether/pentane 1:2 followed by ether/pentane 1:1 aseluent.

NMR: δ=1.1-1.8 (m, 8H), 2.10 (bs, 1H), 3.05 (t, 2H), 3.39 (t, 2H), 4.00(s, 2H), 4.12 (s, 2H), 5.10 (bd, 2H), 7.0-7.5 (m, 15H).

PREPARATION 473-Pentaceylaminocarbonyloxy-1-[6-(triphenylmethoxy)hexyloxy]-2-methylenepropane

A mixture of 3-[6-(triphenylmethoxy)hexyloxy]-2-methylenepropan-1-ol(from Preparation 46) (1.2 g), pentadecyl isocyanate (0.78 g) and4-dimethylaminopyridine (0.07 g) in methylene chloride (5 ml) wasstirred for 5 hours at 22° C. The mixture was evaporated to dryness invacuo, and the residue was extracted with ether (2×20 ml). The etherextracts were evaporated to dryness in vacuo, and the product waspurified through a column of silica gel 60 (70-230 mesh, 15 g) elutingwith ether/methylene chloride 1:1. Further purification was achieved bychromatography on Waters PrepLC®/System 500A using a prepPAK®-500/SILICAcartridge with ether/methylene chloride/pentane 1:1:3 as eluent.

NMR: δ=0.88 (t, 3H), 1.25 (s, 26H), 1.2-1.8 (m, 8H), 3.15 (m, 4H), 3.38(t, 2H), 3.95 (s, 2H), 4.57 (s, 2H), 4.70 (m, 1H), 5.16 (s, 2H), 7.2-7.5(m, 15H).

PREPARATION 483-Octadecylaminocarbonyloxy-1-[6-(triphenylmethoxy)hexyloxy]-2-methylenepropane

Following the procedure described in Preparation 47, but replacingpentadecyl isocyanate with octadecyl isocyanate, the desired product wasobtained.

NMR: δ=0.88 (t, 3H), 1.26 (s, 32H), 1.1-1.7 (m, 8H), 3.10 (m, 4H), 3.38(t, 2H), 3.95 (s, 2H), 4.57 (s, 2H), 4.60 (m, 1H), 5.17 (s, 2H), 7.1-7.4(m, 15H).

PREPARATION 493-Octadecyloxycarbonyloxy-1-[6-(triphenylmethoxy)hexyloxyl]-2-methylenepropane

A mixture of 3-[6-(triphenylmethoxy)hexyloxy]-2-metylenepropane-1-ol(from Preparation 46) (1.5 g) and pyridine (4.5 ml) in methylenechloride (15 ml) was cooled in an ice/water bath andoctadecyloxycarbonyl chloride (1.3 g) was added. After stirring for 10minutes at 0° C. the temperature was raised to 22° C. for 5 hours. Ether(15 ml) was added, and the mixture was filtered. The filtrate wasevaporated to dryness in vacuo, and the residue was purified through acolumn of silica gel 60 (70-230 mesh, 15 g) eluting with ether/methylenechloride 1:1. Further purification was achieved by chromatography onWaters PrepLC®/System 500A using a prepPAK®-500/SILICA cartridge withether/methylene chloride/pentane 1:1:3 as eluent.

NMR: δ=0.88 (t, 3H), 1.26 (s, 32H), 1.0-1.8 (m, 8H), 3.05 (t, 2H), 3.38(t, 2H), 3.97 (s, 2H), 4.12 (t, 2H), 4.63 (s, 2H), 5.25 (s, 2H), 7.1-7.5(m, 15H).

PREPARATION 503-Hexadecyloxycarbonyloxy-1-[6-(triphenylmethoxy)hexyloxy]-2-methylenepropane

Following the procedure described in Preparation 49, but replacingoctadecyloxycarbonyl chloride with hexadecyloxycarbonyl chloride, thedesired product was obtained.

NMR: δ=0.88 (t, 3H), 1.2-1.8 (m, 8H), 1.26 (s, 28H), 3.05 (t, 2H), 3.38(t, 2H), 3.97 (s, 2H), 4.12 (t, 2H), 4.63 (s, 2H), 5.25 (s, 2H), 7.1-7.5(m, 15H).

PREPARATION 513-Hexadecyloxycarbonyloxy-1-(6-hydroxyhexyloxy)-2-methylenepropane

3-Hexadecyloxycarbonyloxy-1-[6-(triphenylmethoxy)hexyloxy]-2-methylenepropane(from Preparation 50) (1.95 g), 4-toluenesulfonic acid monohydrate (60mg) and water (0.15 ml) were stirred in methylene chloride (30 ml) for24 hours at 22° C. The reaction mixture was neutralized with saturatedaqueous sodium hydrogencarbonate, dried over magnesium sulfate, filteredand evaporated in vacuo to dryness. Purification was achieved bychromatography on Waters PrepLC®/System 500A using a prepPAK®-500cartridge with ether/chloroform/pentane 1:1:10 followed byether/chloroform 1:1 as eluents.

NMR: δ=0.88 (t, 3H), 1.16 (s, 30H), 1.2-1.8 (m, 7H), 3.41 (t, 2H), 3.63(t, 2H), 3.98 (s, 2H), 4.13 (t, 2H), 4.64 (s, 2H), 5.23 (s, 2H).

PREPARATION 523-Octadecyloxycarbonyloxy-1-(6-hydroxyhexyloxy)-2-methylenepropane

Following the procedure described in Preparation 51, but replacing3-hexadcyloxycarbonyloxy-1-[6-(triphenylmethoxy)hexyloxy]-2-methylenepropanewith3-octadecyloxycarbonyloxy-1-[6-(triphenylmethoxy)hexyloxy]-2-methylenepropane(from Preparation 49), the desired product was obtained.

NMR: δ=0.87 (t, 3H), 1.25 (s, 32H), 1.2-1.8 (m, 9H), 3.41 (t, 2H), 3.63(t, 2H), 4.07 (s, 2H), 4.13 (t, 2h), 4.64 (s, 2H), 5.23 (s, 2H).

PREPARATION 533-Octadecylaminocarbonyloxy-1-(6-hydroxyhexyloxy)-2-methylenepropane

Following the procedure described in Preparation 51, but replacing3-hexadecyloxycarbonyloxy-1-[6-(triphenylmethoxy)hexyloxy]-2-methylenepropanewith3-octadecylaminocarbonyloxy-1-[6-(triphenylmethoxy)hexyloxy]-2-methylenepropane(from Preparation 48), the desired product was obtained.

NMR: δ=0.87 (t, 3H), 1.25 (s, 32H), 1.0-1.8 (m, 8H), 3.14 (m, 3H), 3.40(t, 2H), 3.62 (t, 2H), 3.95 (s, 2H), 4.56 (s, 2H), 4.60 (bs, 1H), 5.16(s, 2H).

PREPARATION 543-Pentadecylaminocarbonyloxy-1-(6-hydroxyhexyloxy)-2-methylenepropane

Following the procedure described in Preparation 51, but replacing3-hexadecyloxycarbonyloxy-1-[6-(triphenylmethoxy)hexyloxy]-2-methylenepropanewith3-pentadecylaminocarbonyloxy-1-[6-(triphenylmethoxy)hexyloxy]-2-methylenepropane,the desired product was obtained.

NMR: δ=0.87 (t, 3H), 1.25 (s, 26H), 1.2-1.7 (m, 8H), 1.86 (s, 1H), 3.14(q, 2H), 3.41 (t, 2H), 3.62 (t, 2H), 3.96 (s, 2H), 4.58 (s, 2H), 4.70(m, 1H), 5.17 (s, 2H).

PREPARATION 553-Hexadecyloxycarbonyloxy-1-[6-(methanesulfonyloxy)hexyloxy]-2-methylenepropane

3-Hexadecyloxycarbonyloxy-1-(6-hydroxyhexyloxy)-2-methylenepropane (fromPreparation 51) (0.54 g) and methanesulfonyl chloride (0.20 g) werestirred in methylene chloride at 0° C. Pyridine (6 ml) was added andstirring continued for 15 minutes at 0° C. and for 2.5 hours at 22° C.Methylene chloride (10 ml) was added, and the organic phase was washedwith water (3×15 ml), dried over magnesium sulfate, filtered andevaporated in vacuo to dryness. Purification was achieved bychromatography on silica gel 60 (70-230 mesh, 15 g) eluting withchloroform/ether/pentane 1:1:10 followed by chloroform/ether 1:1.

NMR: δ=0.87 (t, 3H), 1.25 (s, 28H), 1.0-1.8 (m, 8H), 2.99 (s, 3H), 3.41(t, 2H), 3.98 (s, 2H), 4.12 (t, 2H), 4.22 (t, 2H), 4.64 (s, 2H), 5.23(s, 2H).

PREPARATION 563-Octadecyloxycarbonyloxy-1-[6-(methanesulfonyloxy)hexyloxy]-2-methylenepropane

Following the procedure described in Preparation 55, but replacing3-hexadecyloxycarbonyloxy-1-(6-hydroxyhexyloxy)-2-methylenepropane with3-octadecyloxycarbonyloxy-1-(6-hydroxyhexyloxy)-2-methylenepropane (fromPreparation 52), the desired product was obtained.

NMR: δ=0.88 (t, 3H), 1.26 (s, 32H), 1.0-2.0 (m, 8H), 3.00 (s, 3H), 3.41(t, 2H), 3.98 (s, 2H), 4.13 (t, 2H), 4.22 (t, 2H), 4.64 (s, 2H), 5.23(s, 2H).

PREPARATION 573-pentadecylaminocarbonyloxy-1-[6-(methanesulfonyloxy)hexyloxy]-2-methylenepropane

Following the procedure described in Preparation 55, but replacing3-hexadecyloxycarbonyloxy-1-(6-hydroxyhexyloxy)-2-methylenepropane with3-pentadecylaminocarbonyloxy-1-(6-hydroxyhexyloxy)-2-methylenepropane(from Preparation 54), the desired product was obtained.

NMR: δ=0.88 (t, 3H), 1.26 (s, 26H), 1.1-1.9 (m, 8H), 3.00 (s, 3H), 3.16(q, 2H), 3.41 (t, 2H), 3.96 (s, 2H), 4.22 (t, 2H), 4.58 (s, 2H), 4.70(m, 1H), 5.18 (s, 2H).

PREPARATION 583-Octadecylaminocarbonyloxy-1-[6-(methanesulfonyloxy)hexyloxy]-2-methylenepropane

Following the procedure described in Preparation 55, but replacing3-hexadecyloxycarbonyloxy-1-(6-hydroxyhexyloxy)-2-methylenepropane with3-octadecylaminocarbonyloxy-1-(6-hydroxyhexyloxy)-2-methylenepropane(from Preparation 53), the desired product was obtained.

NMR: δ=0.87 (t, 3H), 1.26 (s, 32H), 1.0-1.8 (m, 8H), 2.99 (s, 3H), 3.12(q, 2H), 3.40 (t, 2H), 3.96 (s, 2H), 4.22 (t, 2H), 4.57 (s, 2H), 4.70(bs, 1H), 5.18 (bs, 2H).

EXAMPLE 11-Hexadecyloxy-3-[4-(trimethylammonio)butoxy]-2-methylenepropanemethanesulfonate

1-Hexadecyloxy-3-[4-(methanesulfonyloxy)butoxy]-2-methylenepropane (fromPreparation 7) (1.77 g) was refluxed with 33% trimethylamine in ethanolat 50° C. for 4 hours. Excess trimethylamine and ethanol were removed invacuo. The product was recrystallized from chloroform/acetone.

Mp. 125°-131° C.

Elemental analysis: calculated C 64.44%, H 11.40%, N 2.68%, S 6.15%,found C 64.39%, H 11.37%, N 2.72%, S 6.05%.

NMR: δ=0.9 (t, 3H), 1-2 (m, 32H), 2.71 (s, 3H), 3.32 (s, 9H), 3.2-3.7(m, 6H), 3.94 (bs, 4H), 5.14 (bs, 2H).

EXAMPLE 2 1-Hexadecyloxy-3-[4-(3-thiazolio)butoxy]-2-methylenepropanemethanesulfonate

1-Hexadecyloxy-3-[4-(methanesulfonyloxy)butoxy]-2-methylenepropane (fromPreparation 7) (2.5 g) was heated with thiazole (2 ml) at 60° C. for 4days. Excess thiazole was removed in vacuo.

NMR: δ=0.9 (t, 3H), 1-1.8 (m, 30H), 1.9-2.3 (m, 2H), 2.76 (s, 3H),3.2-3.5 (m, 4H), 3.94 (bs, 4H), 4.76 (t, 2H), 5.14 (bs, 2H), 8.4 (m,2H), 10.7 (bs, 1H).

EXAMPLE 31-Hexadecyloxy-3-(4-[5-(2-hydroxyethyl)-4-methyl-3-thiazolio]butoxy)-2-methylenepropanemethanesulfonate

1-Hexadecyloxy-3-[4-(methanesulfonyloxy)butoxy]-2-methylenepropane (fromPreparation 7) (0.30 g) was heated with5-(2-hydroxyethyl)-4-methylthiazole at 56° C. for 5 days. Excess5-(2-hydroxyethyl)-4-methylthiazole was removed in vacuo.

NMR: δ=0.9 (t, 3H), 1-2.2 (m, 32H), 2.50 (s, 3H), 2.69 (s, 3H), 3.05 (t,2H), 3.2-3.5 (m, 4H), 3.85 (m, 2H), 3.94 (s, 4H), 4.5 (t, 2H), 5.14 (bs,2H), 10.29 (s, 1H).

EXAMPLE 4 1-Hexadecyloxy-3-[4-(1-pyridinio)butoxy]-2-methylenepropanemethanesulfonate

1-Hexadecyloxy-3-[4-(methanesulfonyloxy)butoxy]-2-methylenepropane (fromPreparation 7) (1.6 g) was heated with dry pyridine (50 ml) at 50° C.for 28 hours. Excess pyridine was removed in vacuo. The product wasrecrystallized from chloroform/acetone.

NMR: δ=0.9 (t, 3H), 1.1-1.8 (m, 30H), 1.95-2.5 (m, 2H), 2.75 (s, 3H),3.25-3.55 (m, 4H), 3.93 (bs, 4H), 4.89 (t, 2H), 5.14 (bs, 2H), 8.1 (t,2H), 8.5 (t, 1H), 9.3 (d, 2H).

EXAMPLE 5 1-Hexadecyloxy-3-[5-(1-pyridinio)pentyloxy]-2-methylenepropanemethanesulfonate

Following the procedure described in Example 4, but replacing1-hexadecyloxy-3-[4-(methanesulfonyloxy)butoxy]-2-methylenepropane with1-hexadecyloxy-3-[5-(methanesulfonyloxy)pentyloxy]-2-methylenepropane(from Preparation 8), the desired product was obtained.

NMR: δ=0.9 (t, 3H), 1-1.8 (m, 32H), 1.85-2.3 (m, 2H), 2.75 (s, 3H), 3.39(m, 4H), 3.92 (bs, 4H), 4.83 (t, 2H), 5.13 (m, 2H), 8.10 (t, 2H), 8.5(t, 1H), 9.3 (d, 2H).

EXAMPLE 61-Octadecylaminocarbonyloxy-3-[6-(1-pyridinio)hexanoyloxy]-2-methylenepropanebromide

1-Octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropane(from Preparation 9) (0.84 g) was dissolved in dry pyridine (20 ml) andheated to 60° C. for 22 hours. Excess pyridine was removed in vacuo.

NMR: δ=0.9 (t, 3H), 1.1-1.9 (m, 36H), 1.9-2.25 (m, 2H), 2.36 (t, 2H),3.16 (m, 2H), 4.57 (s, 4H), 5.03 (t, 3H), 5.23 (m, 2H), 8.17 (t, 2H),8.57 (t, 1H), 9.61 (d, 2H).

EXAMPLE 71-Octadecylaminocarbonyloxy-3-[5-(1-pyridinio)pentanyloxy]-2-methylenepropanebromide

Following the procedure described in Example 6, but replacing1-octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropanewith1-octadecylaminocarbonyloxy-3-(5-bromopentanoyloxy)-2-methylenepropane(from Preparation 10), the desired product was obtained.

NMR: δ=0.9 (t, 3H), 1.1-2.2 (m, 36H), 2.46 (t, 2H), 3.15 (m, 2H), 4.57(bs, 4H), 5.1 (m, 2H), 5.23 (m, 2H), 8.1 (t, 2H), 8.5 (t, 1H), 9.6 (d,2H).

EXAMPLE 81-Octadecylaminocarbonyloxy-3-[8-(1-pyridinio)octanoyloxy]-2-methylenepropanebromide

Following the procedure described in Example 6, but replacing1-octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropanewith1-octadecylaminocarbonyloxy)-3-(8-bromooctanoyloxy)-2-methylenepropane(from Preparation 11), the desired product was obtained.

NMR: δ=0.88 (t, 3H), 1.1-1.8 (m, 40H), 1.8-2.2 (m, 2H), 2.32 (t, 2H),3.15 (m, 2H), 4.58 (bs,4H), 4.9 (m, 1H), 5.03 (t, 2H), 5.24 (bs, 2H),8.15 (t, 2H), 8.54 (t, 1H), 9.55 (d, 2H).

EXAMPLE 91-Octadecylaminocarbonyloxy-3-[6-(3-thiazolio)hexanoyloxy]-2-methylenepropanebromide

1-Octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropane(from Preparation 9) (0.55 g) and thiazole (2.5 ml) were heated to 110°C. for 4 hours. The reaction mixture was evaporated to dryness in vacuo.

NMR: δ=0.88 (t, 3H), 1.0-1.8 (m, 36H), 1.8-2.2 (m, 2H), 2.37 (t, 2H),3.15 (m, 2H), 4.58 (bs, 4H), 4.88 (t, 2H), 5.0 (m, 1H), 5.23 (bs, 2H),8.37 (bs, 1H), 8.63 (bs, 1H), 11.15 (bs, 1H).

EXAMPLE 101-Octadecylaminocarbonyloxy-3-[5-(3-thiazolio)pentanoyloxy]-2-methylenepropanebromide

Following the procedure described in Example 9, but replacing1-octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropanewith1-octadecylaminocarbonyloxy-3-(5-bromopentanoyloxy)-2-methylenepropane,the desired product was obtained.

NMR: δ=0.88 (t, 3H), 1.0-1.9 (m, 34H), 1.9-2.3 (m, 2H), 2.46 (t, 2H),3.15 (m, 2H), 4.58 (bs, 4H), 4.7-5.1 (m, 3H), 5.24 (bs, 2H), 8.35 (m,1H), 8.66 (m, 1H), 11.15 (bs, 1H).

EXAMPLE 111-Octadecylaminocarbonyloxy-3-[8-(3-thiazolio)octanoyloxy]-2-methylenepropanebromide

Following the procedure described in Example 9, but replacing1-octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropanewith1-octadecylaminocarbonyloxy-3-(8-bromooctanoyloxy)-2-methylenepropane(from Preparation 11), the desired product was obtained.

NMR: δ=0.88 (t, 3H), 1-1.75 (m, 40H), 1.75-2.2 (m, 2H), 2.33 (t, 2H),3.15 (m, 2H), 4.58 (bs, 4H), 4.87 (t, 2H), 4.9 (m, 1H), 5.24 (bs, 2H),8.41 (bs, 1H), 8.61 (bs, 1H), 11.18 (bs, 1H).

EXAMPLE 121-Pentadecylaminocarbonyloxy-3-[6-(3-thiazolio)hexanoyloxy]-2-methylenepropanebromide

Following the procedure described in Example 9, but replacing1-octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropanewith1-pentadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropane(from Preparation 12), the desired product was obtained.

NMR: δ=0.88 (t, 3H), 1.1-2.0 (m, 30H), 2.1 (m, 2H), 2.37 (t, 2H), 3.15(q, 2H), 4.58 (bs, 4H), 4.85 (t, 2H), 4.9 (m, 1H), 5.28 (bs, 2H), 8.36(m, 1H), 8.63 (d, 1H), 10,84 (bs, 1H).

EXAMPLE 131-Pentadecylaminocarbonyloxy-:3-[8-(3-thiazolio)octanoyloxy]-2-methylenepropanebromide

Following the procedure described in Example 9, but replacing1-octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropanewith1-pentanoylaminocarbonyloxy-3-(8-bromooctanoyloxy)-2-methylenepropane(from Preparation 13), the desired product was obtained.

NMR: δ=0.88 (t, 3H), 1.1-2.2 (m, 36H), 2.33 (t, 2H), 3.15 (q, 2H), 4.58(bs, 4H), 4.86 (t, 2H), 4.8 (m, 1H), 5.24 (bs, 2H), 8.37 (m, 1H), 8.53(d, 1H), 10.83 (bs, 1H).

EXAMPLE 141-Octadecylaminocarbonyloxy-3-[6-(trimethylammonio)hexanoyloxy]-2-methylenepropanebromide

1-Octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropane(from Preparation 9) (0.84 g) was dissolved in 33% trimethylamine inethanol (30 ml) and heated to 60° C. in a sealed flask for 5 hours.Excess trimethylamine and ethanol were removed in vacuo.

NMR: δ=0.9 (t, 3H), 1.1-2.0 (m, 38H), 2.39 (t, 2H), 3.15 (m, 2H), 3.46(s, 9H), 3.5-3.8 (m, 2H), 4.59 (bs, 4H), 4.9 (m, 1H), 5.25 (bs, 2H).

EXAMPLE 151-Octadecylaminocarbonyloxy-3-[5-(trimethylammonio)pentanoyloxy]-2-methylenepropanebromide

Following the procedure described in Example 14, but replacing1-octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropanewith1-octadecylaminocarbonyloxy-3-(5-bromopentanoyloxy)-2-methylenepropane(from Preparation 10), the desired product was obtained.

NMR: δ=0.9 (t, 3H), 1.1-2.0 (m, 36H), 2.48 (t, 2H), 3.15 (m, 2H), 3.45(s, 9H), 3.75 (m, 2H), 4.6 (m, 4H), 4.9 (m, 1H), 5.25 (bs, 2H).

EXAMPLE 161-Octadecylaminocarbonyloxy-3-[4-(1-pyridinio)butylaminocarbonyloxy]-2-methylenepropanebromide

Following the procedure described in Example 6, but replacing1-octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropanewith1-octadecylaminocarbonyloxy-3-(4-bromobutylaminocarbonyloxy)-2-methylenepropane(from Preparation 14), the desired product was obtained.

NMR: δ=0.9 (t, 3H), 1.1-1.9 (m, 34H), 1.9-2.3 (m, 2H), 3-3.4 (m, 4H),4.53 (bs, 4H), 5.0 (m, 2H), 5.17 (bs, 2H), 5.3 (m, 1H), 6.35 (m, 1H),8.1 (t, 2H), 8.54 (t, 1H), 9.63 (d, 2H).

EXAMPLE 171-Octadecylaminocarbonyloxy-3-[2-(1-pyridinio)ethylaminocarbonyloxy]-2-methylenepropanebromide

Following the procedure described in Example 6, but replacing1-octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropanewith1-octadecylaminocarbonyloxy-3-(2-bromoethylaminocarbonyloxy)-2-methylenepropane(from Preparation 15), the desired product was obtained.

NMR: δ=0.9 (t, 3H), 1.1-1.7 (m, 32H), 3.13 (m, 2H), 3.8 (m, 2H), 4.45(m, 4H), 5.15 (m, 4H), 5.45 (t, 1H), 7.1 (m, 1H), 8.1 (t, 2H), 8.5 (t,1H), 9.38 (d, 2H).

EXAMPLE 181-Octadecylaminocarbonyloxy-3-[4-(trimethylammonio)butylaminocarbonyloxy]-2-methylenepropanebromide

Following the procedure described in Example 14, but replacing1-octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropanewith1-octadecylaminocarbonyloxy-3-(4-bromobutylaminocarbonyloxy)-2-methylenepropane(from Preparation 14), the desired product was obtained.

NMR: δ=0.9 (t, 3H), 1-2 (m, 36H), 3.2 (m, 4H), 3.40 (bs, 9H), 3.74 (m,2H), 4.56 (bs, 4H), 5.22 (m, 3H), 6.3 (t, 1H).

EXAMPLE 191-Octadecylaminocarbonyloxy-3-[2-(trimethylammonio)ethylaminocarbonyloxy]-2-methylenepropanebromide

Following the procedure described in Example 14, but replacing1-octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropanewith1-octadecylaminocarbonyloxy-3-(2-bromoethylaminocarbonyloxy)-2-methylenepropane(from Preparation 15), the desired product was obtained.

NMR: δ=0.9 (t, 3H), 1.1-1.5 (m, 32H), 3.1 (m, 2H), 3.46 (bs, 9H), 3.79(m, 4H), 4.58 (m, 4H), 5.23 (bs, 2H), 5.25 (m, 1H), 7.1 (m, 1H).

EXAMPLE 201-Hexadecyloxy-3-[4-(trimethylammonio)butanoyloxy]-2-methylenepropanebromide

Following the procedure described in Example 14, but replacing1-octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropanewith 1-hexadecyloxy-3-(4-bromobutanoyloxy)-2-methylenepropane (fromPreparation 20), the desired product was obtained.

NMR: δ=0.9 (t, 3H), 1.1-1.8 (m, 28H), 2.1 (m, 2H), 2.57 (t, 2H), 3.39(m, 2H), 3.49 (bs, 9H), 3.75 (m, 2H), 3.96 (bs, 2H), 4.61 (bs, 2H), 5.20(m, 2H).

EXAMPLE 211-Hexadecyloxy-3-[6-(trimethylammonio)hexanoyloxy]-2-methylenepropane

Following the procedure described in Example 14, but replacing1-octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropanewith 1-hexadecyloxy-3-(6-bromohexanoyloxy)-2-methylenepropane (fromPreparation 18), the desired product was obtained.

NMR: δ=0.9 (t, 3H), 1.1-2.0 (m, 34H), 2.38 (t, 2H), 3.3-3.7 (m, 4H),3.46 (bs, 9H), 3.96 (bs, 2H), 4.58 (bs, 2H), 5.19 (m, 2H).

EXAMPLE 221-Hexadecyloxy-3-[11-(trimethylammonio)undecanoyloxy)-2-methylenepropanebromide

Following the procedure described in Example 14, but replacing1-octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropanewith 1-hexadecyloxy-3-(11-bromoundecanoyloxy)-2-methylenepropane (fromPreparation 21), the desired product was obtained.

NMR: δ=0.88 (t, 3H), 1.25 (bs, 38H), 1.3-1.8 (m, 6H), 2.34 (t, 2H),3.3-3.6 (m, 4H), 3.47 (s, 9H), 3.97 (bs, 2H), 4.59 (bs, 2H), 5.19 (bs,2H).

EXAMPLE 23 1-Hexadecyloxy-3-(1-pyridinioacetoxy)-2-methylenepropanebromide

1-Hexadecyloxy-3-bromoacetoxy-2-methylenepropane (from Preparation 19)(0.65 g) was dissolved in dry pyridine (20 ml). After 1.5 hours at 22°C. the mixture was evaporated in dryness in vacuo.

NMR: δ=0.87 (t, 3H), 1.25 (bs, 26H), 1.45 (m, 2H), 3.45 (t, 2H), 3.97(bs, 2H), 4.74 (bs, 2H), 5.25 (bs, 2H), 6.28 (bs, 2H), 8.11 (t, 2H),8.57 (t, 1H), 9.40 (d, 2H).

EXAMPLE 241-Hexadecyloxy-3-[6-(1-pyridinio)hexanoyloxy]-2-methylenepropane bromide

Following the procedure described in Example 6, but replacing1-octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropanewith 1-hexadecyloxy-3-(6-bromohexanoyloxy)-2-methylenepropane (fromPreparation 18), the desired product was obtained.

NMR: δ=0.87 (t, 3H), 1.25 (bs, 28H), 1.3-1.5 (m, 4H), 2.1 (m, 2H), 2.36(m, 2H), 3.39 (m, 2H), 3.95 (bs, 2H), 4.56 (bs, 2H), 5.01 (m, 2H), 5.17(bd, 2H), 8.16 (m, 2H), 8.56 (m, 1H), 9.50 (d, 2H).

EXAMPLE 251-Hexadecyloxy-3-[11-(1-pyridinio)undecanoyloxy]-2-methylenepropanebromide

Following the procedure described in Example 6, but replacing1-octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropanewith 1-hexadecyloxy-3-(11-bromoundecanoyloxy)-2-methylenepropane (fromPreparation 21), the desired product was obtained.

NMR: δ=0.87 (t, 3H), 1.2-1.7 (bs, 42H), 2.05 (m, 2H), 2.33 (t, 2H), 3.40(t, 2H), 3.96 (bs, 2H), 4.59 (bs, 2H), 4.99 (t, 2H), 5.19 (bs, 2H), 8.17(t, 2H), 8.55 (m, 1H), 9.50 (d, 2H).

EXAMPLE 261-Hexadecyloxy-3-[4-(trimethylammonio)butylaminocarbonyloxy]-2-methylenepropanebromide

Following the procedure described in Example 14, but replacing1-octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-propane with1-hexadecyloxy-3-(4-bromobutylaminocarbonyloxy)-2-methylenepropane (fromPreparation 16), the desired product was obtained.

NMR: δ=0.88 (t, 3H), 1.26 (bs, 28H), 1.70 (m, 4H), 3.30 (m, 4H), 3.41(m, 9H), 3.73 (t, 2H), 3.96 (bs, 2H), 4.55 (bs, 2H), 5.18 (bs, 2H), 6.00(bt, 1H).

EXAMPLE 271-Hexadecyloxy-3-[2-(trimethylammonio)ethylaminocarbonyloxy]-2-methylenepropanebromide

Following the procedure described in Example 14, but replacing1-octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropanewith 1-hexadecyloxy-3-(2-bromoethylaminocarbonyloxy)-2-methylenepropane(from Preparation 17), the desired product was obtained.

NMR: δ=0.88 (t, 3H), 1.25 (bs, 26H), 1.50 (m, 2H), 3.38 (t, 2H), 3.46(s, 9H), 3.69 (q, 2H), 3.80 (bm, 2H), 3.95 (bs, 2H), 4.57 (bs, 2H), 5.17(bs, 2H), 6.95 (bt, 1H).

EXAMPLE 281-Hexadecyloxy-3-[4-(1-pyridinio)butylaminocarbonyloxy]-2-methylenepropanebromide

Following the procedure described in Example 6, but replacing1-octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropanewith 1-hexadecyloxy-3-(4-bromobutylaminocarbonyloxy)-2-methylenepropane(from Preparation 16), the desired product was obtained.

NMR: δ=0.88 (t, 3H), 1.2-1.9 (m, 32H), 3.20 (q, 2H), 3.38 (t, 2H), 3.95(bs, 2H), 4.54 (bs, 2H), 5.10 (t, 2H), 5.16 (bs, 2H), 5.90 (bt, 1H).

EXAMPLE 291-Hexadecyloxy-3-[2-(1-pyridinio)ethylaminocarbonyloxy]-2-methylenepropanebromide

Following the procedure described in Example 6, but replacing1-octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropanewith 1-hexadecyloxy-3-(2-bromoethylaminocarbonyloxy)-2-methylenepropane(from Preparation 17), the desired product was obtained.

NMR: δ=0.88 (t, 3H), 1.1-1.7 (m, 28H), 3.36 (t, 2H), 3.85 (q, 2H), 3.89(bs, 2H), 4.40 (bs, 2H), 5.11 (bs, 2H), 5.22 (t, 2H), 6.85 (bt, 1H), 8.0(m, 2H), 8.46 (m, 1H), 9.40 (bd, 2H).

EXAMPLE 301-Hexadecanoyloxy-3-[6-(1-pyridinio)hexanoyloxy]-2-methylenepropanebromide

Following the procedure described in Example 6, but replacing1-octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropanewith 1-hexadecanoyloxy-3-(6-bromohexanoyloxy)-2-methylenepropane (fromPreparation 22), the desired product was obtained.

NMR: δ=0.88 (t, 3H), 1.1-2 (m, 30H), 2.12 (m, 2H), 2.35 (m, 4H), 4.58(bs, 4H), 5.05 (t, 2H), 5.25 (bs, 2H), 8.15 (t, 2H), 8.55 (t, 1H), 9.58(d, 2H).

EXAMPLE 311-Hexadecanoyloxy-3-[4-(1-pyridinio)butylaminocarbonyloxy]-2-methylenepropanebromide

Following the procedure described in Example 6, but replacing1-octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropanewith1-hexadecanoyloxy-3-(4-bromobutylaminocarbonyloxy)-2-methylenepropane(from Preparation 23), the desired product is obtained.

EXAMPLE 321-Hexadecylaminothiocarbonyloxy-3-[6-(1-pyridinio)hexanoyloxy]-2-methylenepropanebromide

Following the procedure described in Example 6, but replacing1-octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropanewith1-hexadecylaminothiocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropane(from Preparation 24), the desired product was obtained.

NMR: δ=0.88 (t, 3H), 1.25 (s, 28H), 0.9-2.0 (m, 4H), 2.05 (m, 2H), 2.37(t, 2H), 3.2-3.6 (m, 2H), 4.60 (m, 2H), 4.92 (m, 2H), 4.99 (t, 2H), 5.26(m, 2H), 6.8-7.6 (m, 1H), 8.16 (t, 2H), 8.56 (t, 1H), 9.57 (d, 2H).

EXAMPLE 331-Hexadecyloxycarbonyloxy-3-[6-(1-pyridinio)hexanoyloxyl]-2-methylenepropanebromide

Following the procedure described in Example 6, but replacing1-octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropanewith 1-hexadecyloxycarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropane(from Preparation 25), the desired product was obtained.

NMR: δ=0.88 (t, 3H), 1.25 (s, 28H), 1.0-2.3 (m, 6H), 2.36 (t, 2H), 4.13(t, 2H), 4.59 (s, 2H), 4.63 (s, 2H), 5.05 (t, 2H), 5.29 (s, 2H), 8.16(t, 2H), 8.56 (t, 1H), 9.57 (d, 2H).

EXAMPLE 341-Octadecylaminocarbonyloxy-3-[6-(1-pyridinio)hexanoyloxy]-2-isopropylidenepropanebromide

Following the procedure described in Example 6, but replacing1-octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropanewith1-octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-isopropylidenepropane(from Preparation 27), the desired compound was obtained.

NMR: δ=0.87 (t, 3H), 1.25 (s, 32H), 1.0-2.2 (m, 6H), 1.82 (s, 3H), 1.84(s, 3H), 2.32 (t, 2H), 3.13 (q, 2H), 4.62 (bs, 2H), 4.64 (bs, 2H), 4.70(m, 1H), 5.05 (t, 2H), 8.12 (t, 2H), 8.52 (t, 1H), 9.57 (d, 2H).

EXAMPLE 351-Octadecylaminocarbonyloxy-3-[6-(1-pyridinio)hexanoyloxy]-2-ethylidenepropanebromide

Following the procedure described in Example 6, but replacing1-octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropanewith an approx. 1:1 mixture of E- and Z-isomers of1-octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-ethylidenepropane(from Preparation 29), an approx. 1:1 mixture of E- and Z-isomers of thedesired compound is obtained.

EXAMPLE 361-Hexadecanoyloxy-3-[6-(3-thiazolio)hexanoyloxy]-2-methylenepropanebromide

Following the procedure described in Example 9, but replacing1-octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropanewith 1-hexadecanoyloxy-3-(6-bromohexanoyloxy)-2-methylenepropane (fromPreparation 22), the desired products was obtained.

NMR: δ=0.88 (s, 3H), 1.25 (s, 24H), 1.1-2.1 (m, 8H), 2.34 (m, 4H), 4.58(s, 4H), 4.90 (m, 2H), 5.25 (s, 2H), 8.40 (bs, 1H), 8.64 (bs, 1H), 11.18(bs, 1H).

EXAMPLE 371-Hexadecanoyloxy-3-[8-(1-pyridinio)octanoyloxy]-2-methylenepropanebromide

1-Hexadecanoyloxy-3-(8-bromooctanoyloxy)-2-methylenepropane (fromPreparation 30) (0.80 g) was dissolved in dry pyridine (20 ml) andheated to 100° C. for 8 hours. Excess pyridine was removed in vacuo.

NMR: δ=0.88 (t, 3H), 1.25 (s, 30H), 1.1-2.2 (m, 6H), 2.32 (t, 4H), 4.58(s, 4H), 5.02 (t, 2H), 5.25 (s, 2H), 8.23 (t, 2H), 8.57 (t, 1H), 9.38(d, 2H).

EXAMPLE 381-Octadecylaminocarbonyloxy-3-[8-(1-methyl-3-imidazolio)octanoyloxy]-2-methylenepropaneiodide

1-Octadecylaminocarbonyloxy-3-[8-(1-imidazolyl)octanoyloxy]-2-methylenepropane(from Preparation 33) (0.55 g) was dissolved in chloroform (10 ml).Methyl iodide (6 ml) was added, and the mixture stirred at 22° C. for 24hours. The mixture was evaporated to dryness in vacuo to give thedesired product.

NMR: δ=0.88 (t, 3H), 1.25 (s, 34H), 1.0-1.8 (m, 6H), 1.90 (m, 2H), 2.34(t, 2H), 3.14 (q, 2H), 4.11 (s, 3H), 4.33 (t, 2H), 4.58 (s, 4H), 4.70(bt, 1H), 5.24 (bs, 2H), 7.45 (m, 1H), 7.52 (m, 1H), 9.96 (s, 1H).

EXAMPLE 391-Octadecylaminocarbonyloxy-3-[6-(1-methyl-3-imidazolio)hexanoyloxy]-2-methylenepropanebromide

Following the procedure described in Example 38, but replacing1-octadecylaminocarbonyloxy-3-[8-(1-imidazolyl)octanoyloxy]-2-methylenepropanewith1-octadecylaminocarbonyloxy-3-[6-(1-imidazolyl)hexanoyloxy]-2-methylenepropane(from Preparation 34) the desired product was obtained.

NMR: δ=0.88 (t, 3H), 1.26 (s, 32H), 1.0-2.0 (m, 6H), 2.32 (t, 2H), 3.14(q, 2H), 4.10 (s, 3H), 4.36 (t, 2H), 4.58 (s, 4H), 4.90 (bt, 1H), 5.24(s, 2H), 7.55 (m, 2H), 9.88 (bs, 1H).

EXAMPLE 401-Octadecylaminocarbonyloxy-3-[7-(1-pyridinio)heptylaminocarbonyloxy]-2-methylenepropanebromide

Following the procedure described in Example 37, but replacing1-hexadecanoyloxy-3-(8-bromooctanoyloxy)-2-methylenepropane with1-octadecylaminocarbonyloxy-3-(7-bromoheptylaminocarbonyloxy)-2-methylenepropane(from Preparation 36) the desired product was obtained.

NMR: δ=0.87 (t, 3H), 1.25 (s, 32H), 1.0-1.8 (m, 6H), 2.10 (m, 4H), 3.13(q, 4H), 4.56 (s, 4H), 5.03 (t, 2H), 5.20 (s, 2H), 5.25 (bt, 2H), 8.13(t, 2H), 8.54 (t, 1H), 9.57 (d, 2H).

EXAMPLE 411-Octadecylaminocarbonyloxy-3-[5-(1-pyridinio)pentylaminocarbonyloxy]-2-methylenepropanebromide

Following the procedure described in Example 37, but replacing1-hexadecanoyloxy-3-(8-bromooctanoyloxy)-2-methylenepropane with1-octanoylaminocarbonyloxy-3-(5-bromopentylaminocarbonyloxy)-2-methylenepropane(from Preparation 35) the desired product was obtained.

NMR: δ=0.88 (t, 3H), 1.25 (s, 30H), 1.0-1.7 (m, 6H), 2.10 (m, 2H), 3.12(m, 4H), 4.53 (s, 4H), 4.9-5.2 (m, 5H), 5.85 (m, 1H), 8.10 (bt, 2H),8.51 (bt, 1H), 9.60 (bd, 2H).

EXAMPLE 421-Octadecylaminocarbonyloxy-3-[7-(3-thiazolio)heptylaminocarbonyloxy]-2-methylenepropanebromide

Following the procedure described in Example 9, but replacing1-octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropanewith1-octadecylaminocarbonyloxy-3-(7-bromoheptylaminocarbonyloxy)-2-methylenepropane(from Preparation 36) the desired product was obtained

NMR: δ=0.87 (t, 3H), 1.25 (s, 34H), 1.0-1.8 (m, 6H), 2.0 (m, 2H), 3.16(q, 4H), 4.56 (s, 4H), 4.85 (t, 2H), 5.15 (t, 1H), 5.20 (s, 2H), 5.45(m, 1H), 8.40 (s, 1H), 8.70 (s, 1H), 11.14 (s, 1H).

EXAMPLE 431-Octadecylaminocarbonyloxy-3-[5-(3-thiazolio)pentylaminocarbonyloxy]-2-methylenepropanebromide

Following the procedure described in Example 9, but replacing1-octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropanewith1-octadecylaminocarbonyloxy-3-(5-bromopentylaminocarbonyloxy)-2-methylenepropane(from Preparation 35) the desired product was obtained.

NMR: δ=0.88 (t, 3H), 1.25 (s, 32H), 1.1-1.8 (m, 4H), 2.05 (m, 2H), 3.14(bq, 4H), 4.55 (s, 4H), 4.80 (t, 2H), 5.19 (s, 3H), 5.75 (bs, 1H), 8.30(bs, 1H), 8.70 (bs, 1H), 11.10 (bs, 1H).

EXAMPLE 441-Octadecylaminocarbonyloxy-3-[6-(1-pyridazinio)hexanoyloxy]-2-methylenepropanebromide

1-Octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropane(from Preparation 9) (0.28 g) was dissolved in toluene (5 ml).Pyridazine (0.18 ml) was added, and the mixture was stirred at 64° C.for 20 hours. The mixture was evaporated to dryness in vacuo to give thedesired product.

NMR: δ=0.87 (t, 3H), 1.25 (s, 32H), 1.0-1.8 (m, 4H), 2.30 (m, 4H), 3.14(q, 2H), 4.57 (bs, 4H), 4.8-5.3 (m, 5H), 8.80 (m, 1H), 8.90 (m, 1H),9.50 (bd, 1H), 10.85 (m, 1H).

EXAMPLE 451-Octadecylaminocarbonyloxy-3-[7-(1-pyridinio)heptanoyloxy]-2-methylenepropanebromide

Following the procedure described in Example 37, but replacing1-hexadecanoyloxy-3-(8-bromooctanoyloxy)-2-methylenepropane with1-octadecylaminocarbonyloxy-3-(7-bromoheptanoyloxy)-2-methylenepropane(from Preparation 31) the desired product was obtained.

NMR: δ=0.88 (t, 3H), 1.26 (s, 32H), 1.0-1.8 (m, 6H), 2.07 (m, 2H), 2.33(t, 2H), 3.13 (q, 2H), 4.57 (s, 4H), 5.01 (t, 2H), 5.10 (bs, 1H), 5.22(bs, 2H), 8.15 (t, 2H), 8.54 (t, 1H), 9.56 (d, 2H).

EXAMPLE 461-Octadecylaminocarbonyloxy-3-[7-(3-thiazolio)heptanoyloxy]-2-methylenepropanebromide

Following the procedure described in Example 9, but replacing1-octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropanewith1-octadecylaminocarbonyloxy-3-(7-bromoheptanoyloxy)-2-methylenepropane(from Preparation 31) the desired product was obtained.

M.p. 55°-56° C. (from acetone/ether).

Elemental analysis: calculated for C₃₃ H₅₉ BrN₂ O₄ S, H₂ O: C 58.47%, H9.07%, Br 11.79%, N 4.13%, S 4.73%, H₂ O 2.65%, found C 58.31%, H 9.01%,Br 11.53%, N 4.18%, S 4.54%, H₂ O 2.74%. Hygroscopic.

NMR: δ=0.88 (t, 3H), 1.25 (s, 32H), 1.0-2.0 (m, 6H), 2.10 (m, 2H), 2.35(t, 2H), 3.14 (q, 2H), 4.58 (s, 4H), 4.88 (t, 2H), 5.02 (m, 1H), 5.24(s, 2H), 8.43 (m, 1H), 8.69 (d, 1H), 11.15 (s, 1H).

EXAMPLE 471-Octadecylaminocarbonyloxy-3-[7-(3-thiazolio)heptanoyloxy]-2-methylenepropanemethanesulfate

Following the procedure described in Example 9, but replacing1-octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropanewith1-octadecylaminocarbonyloxy-3-[7-(methanesulfonyloxy)heptanoyloxy]-2-methylenepropane(from Preparation 32), the desired product was obtained.

NMR: δ=0.88 (t, 3H), 1.26 (s, 32H), 1.0-1.8 (m, 6H), 2.0 (m, 2H), 2.33(t, 2H), 2.76 (t, 3H), 3.16 (q, 2H), 4.58 (s, 4H), 4.70 (t, 2H), 5.0 (t,1H), 5.23 (s, 2H), 8.35 (m, 1H), 8.43 (m, 1H), 10.72 (bs, 1H).

EXAMPLE 481-Pentadecylaminocarbonyloxy-3-[8-(1-pyridinio)octanoyloxy]-2-methylenepropanebromide

Following the procedure described in Example 37, but replacing1-hexadecanoyloxy-3-(8-bromooctanoyloxy)-2-methylenepropane with1-pentadecylaminocarbonyloxy-3-(8-bromooctanoyloxy)-2-methylenepropane(from Preparation 13), the desired product was obtained.

NMR: δ=0.87 (s, 3H), 1.25 (s, 28H), 1.1-1.9 (m, 6H), 2.05 (m, 2H), 2.32(m, 2H), 3.16 (q, 2H), 4.58 (s, 4H), 4.95 (m, 3H), 5.24 (s, 2H), 8.17(m, 2H), 8.57 (t, 1H), 9.60 (d, 2H).

EXAMPLE 491-Pentadecylaminocarbonyloxy-3-[6-(1-pyridinio)hexanoyloxy]-2-methylenepropanebromide

Following the procedure described in Example 37, but replacing1-hexadecanoyloxy-3-(8-bromooctanoyloxy)-2-methylenepropane with1-pentadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropane(from Preparation 12), the desired product was obtained.

NMR: δ=0.87 (s, 3H), 1.25 (s, 26H), 1.0-1.9 (m, 4H), 2.08 (m, 2H), 2.36(t, 2H), 3.16 (q, 2H), 4.57 (s, 4H), 5.00 (m, 3H), 5.22 (s, 2H), 8.13(t, 2H), 8.52 (t, 1H), 9.55 (d, 2H).

EXAMPLE 501-Hexadecylaminothiocarbonyloxy-3-[6-(3-thiazolio)hexanoyloxy]-2-methylenepropanebromide

Following the procedure described in Example 9, but replacing1-octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropanewith1-hexadecylaminothiocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropane(from Preparation 24), the desired product was obtained.

NMR: δ=0.87 (t, 3H), 1.25 (s, 26H), 1.0-2.2 (m, 8H), 2.38 (t, 2H),3.2-3.7 (m, 2H), 4.61 (bs, 2H), 4.8-5.1 (m, 4H), 5.30 (m, 2H), 11.20(bs, 1H).

EXAMPLE 511-Octadecyloxycarbonyloxy-3-[7-(3-thiazolio)heptanoyloxy]-2-methylenepropanebromide

Following the procedure described in Example 9, but replacing1-octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropanewith1-octadecyloxycarbonyloxy-3-(7-bromoheptanoyloxy)-2-methylenepropane(from Preparation 38), the desired product was obtained.

NMR: δ=0.88 (t, 3H), 1.26 (s, 32H), 1.0-1.8 (m, 6H), 2.05 (m, 2H), 2.34(t, 2H), 4.13 (t, 2H), 4.61 (s, 2H), 4.63 (s, 2H), 4.85 (t, 2H), 5.30(s, 2H), 8.40 (s, 1H), 8.64 (bd, 1H), 11.15 (bs, 1H).

EXAMPLE 521-Hexadecyloxycarbonyloxy-3-[8-(1-pyridinio)octanoyloxy]-2-methylenepropanebromide

Following the procedure described in Example 37, but replacing1-hexadecanoyloxy-3-(8-bromooctanoyloxy)-2-methylenepropane with1-hexadecyloxycarbonyloxy-2-(8-bromooctanoyloxy)-2-methylenepropane(from Preparation 39) the desired product was obtained.

NMR: δ=0.88 (t, 3H), 1.25 (s, 28H), 1.0-2.0 (m, 8H), 2.10 (m, 2H), 2.33(t, 2H), 4.13 (t, 2H), 4.60 (s, 2H), 4.63 (s, 2H), 5.03 (t, 2H), 5.29(s, 2H), 8.17 (t, 2H), 8.57 (t, 1H), 9.58 (d, 2H).

EXAMPLE 531-Hexadecyloxycarbonyloxy-3-[8-(3-thiazolio)octanoyloxy]-2-methylenepropanebromide

Following the procedure described in Example 9, but replacing1-octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropanewith 1-hexadecyloxycarbonyloxy-3-(8-bromooctanoyloxy)-2-methylenepropane(from Preparation 39) the desired product was obtained.

NMR: δ=0.88 (t, 3H), 1.25 (s, 28H), 1.0-2.0 (m, 8H), 2.10 (m, 2H), 2.33(t, 2H), 4.13 (t, 2H), 4.61 (s, 2H), 4.64 (s, 2H), 4.88 (t, 2H), 5.31(s, 2H), 8.45 (bs, 1H), 8.65 (d, 1H), 11.20 (bs, 1H).

EXAMPLE 541-Hexadecyloxycarbonyloxy-3-[6-(3-thiazolio)hexanoyloxy]-2-methylenepropanebromide

Following the procedure described in Example 9, but replacing1-octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropanewith 1-hexadecyloxycarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropane(from Preparation 25) the desired product was obtained.

NMR: δ=0.88 (t, 3H), 1.25 (s, 28H), 1.0-2.2 (m, 6H), 2.37 (t, 2H), 4.13(t, 2H), 4.61 (bs, 4H), 4.90 (t, 2H), 5.31 (bs, 2H), 8.40 (m, 1H), 11.15(bs, 1H).

EXAMPLE 551-Octadecylaminocarbonyloxy-3-[8-(1-pyridinio)octanoyloxy]-2-isopropylidenepropanebromide

Following the procedure described in Example 37, but replacing1-hexadecanoyloxy-3-(8-bromooctanoyloxy)-2-methylenepropane with1-octadecylaminocarbonyloxy-3-(8-bromooctanoyloxy)-2-isopropylidenepropane(from Preparation 40) the desired product was obtained.

NMR: δ=0.88 (t, 3H), 1.25 (s, 36H), 1.1-2.2 (m, 6H), 1.82 (s, 3H), 1.84(s, 3H), 2.27 (t, 2H), 3.13 (q, 2H), 4.63 (bs, 4H), 4.75 (bt, 1H), 5.03(t, 2H), 8.55 (m, 1H), 9.57 (bd, 2H).

EXAMPLE 561-Octadecylaminocarbonyloxy-3-[6-(3-thiazolio)hexanoyloxy]-2-isopropylidenepropanebromide

Following the procedure described in Example 9, but replacing1-octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropanewith1-octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy-2-isopropylidenepropane(from Preparation 27) the desired product was obtained.

NMR: δ=0.87 (t, 3H), 1.25 (s, 32H), 1.0-2.2 (m, 6H), 1.83 (bs, 6H), 2.33(t, 2H), 3.13 (q, 2H), 4.63 (bs, 2H), 4.65 (bs, 2H), 4.89 (m, 3H), 8.40(m, 1H), 8.65 (bd, 1H), 11.16 (bs, 1H).

EXAMPLE 571-Octadecylaminocarbonyloxy-3-[8-(3-thiazolio)octanoyloxy]-2-isopropylidenepropanebromide

Following the procedure described in Example 9, but replacing1-octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropanewith1-octadecylaminocarbonyloxy-3-(8-bromooctanoyloxy)-2-isopropylidenepropane(from Preparation 40) the desired product was obtained.

NMR: δ=0.88 (t, 3H), 1.25 (s, 36H), 1.0-2.1 (m, 6H), 1.83 (s, 3H), 1.84(s, 3H), 2.28 (t, 2H), 3.13 (q, 2H), 4.64 (bs, 2H), 4.66 (bs, 2H), 4.87(m, 3H), 8.41 (m, 1H), 8.61 (m, 1H), 11.18 (bs, 1H).

EXAMPLE 581-Pentadecylaminocarbonyloxy-3-[6-(1-pyridinio)hexanoyloxy]-2-isopropylidenebromide

Following the procedure described in Example 37, but replacing1-hexadecanoyloxy-3-(8-bromooctanoyloxy)-2-methylenepropane with1-pentadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropane(from Preparation 43) the desired product was obtained.

NMR: δ=0.87 (t, 3H), 1.25 (s, 26H), 1.1-2.2 (m, 6H), 1.82 (s, 3H), 1.84(s, 3H), 2.32 (t, 2H), 3.15 (q, 2H), 4.63 (s, 2H), 4.65 (s, 2H), 4.8(bs, 1H), 5.05 (t, 2H), 8.12 (t, 2H), 8.50 (m, 1H), 9.57 (d, 2H).

EXAMPLE 591-Pentadecylaminocarbonyloxy-3-[8-(1-pyridinio)octanoyloxy]-2-isopropylidenepropanebromide

Following the procedure described in Example 37, but replacing1-hexadecanoyloxy-3-(8-bromooctanoyloxy)-2-methylenepropane withpentadecylaminocarbonyloxy-3-(8-bromooctanoyloxy)-2-isopropylidenepropane(from Preparation 42) the desired product was obtained.

NMR: δ=0.88 (t, 3H), 1.25 (s, 30H), 1.2-2.1 (m, 6H), 1.82 (s, 3H), 1.84(s, 3H), 2.28 (t, 2H), 3.13 (q, 2H), 4.65 (bs, 4H), 4.70 (m, 1H), 5.03(t, 2H), 8.15 (t, 2H), 8.55 (t, 1H), 9.55 (d, 2H).

EXAMPLE 601-Pentadecylaminocarbonyloxy-3-[6-(3-thiazolio)hexanoyloxy]-2-isopropylidenepropanebromide

Following the procedure described in Example 9, but replacing1-octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropanewith1-pentadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-isopropylidenepropane(from Preparation 43) the desired product was obtained.

NMR: δ=0.88 (t, 3H), 1.26 (s, 26H), 1.1-2.2 (m, 6H), 1.82 (s, 3H), 1.84(s, 3H), 2.32 (t, 2H), 3.14 (q, 2H), 4.65 (s, 4H), 4.88 (m, 3H), 8.41(m, 1H), 8.66 (m, 1H), 11.16 (bs, 1H).

EXAMPLE 611-Pentadecylaminocarbonyloxy-3-[8-(3-thiazolio)octanoyloxy]-2-isopropylidenepropanebromide

Following the procedure described in Example 9, but replacing1-octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropanewith1-pentadecylaminocarbonyloxy-3-(8-bromooctanoyloxy)-2-isopropylidenepropane(from Preparation 42) the desired product was obtained.

NMR: δ=0.88 (t, 3H), 1.25 (s, 30H), 1.0-2.2 (m, 6H), 1.83 (s, 3H), 1.84(s, 3H), 2.32 (t, 2H), 3.14 (q, 2H), 4.65 (bs, 4H), 4.88 (m, 3H), 8.42(m, 1H), 8.62 (m, 1H), 11.17 (bs, 1H).

EXAMPLE 621-Tridecylaminocarbonyloxy-(3-[6-(1-pyridinio)hexanoyloxy]-2-methylenepropanebromide

Following the procedure described in Example 37, but replacing1-hexadecanoyloxy-3-(8-bromooctanoyloxy)-2-methylenepropane with1-tridecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropanefrom Preparation 45) the desired product was obtained.

NMR: δ=0.88 (t, 3H), 1.25 (s, 20H), 1.0-2.0 (m, 6H), 2.15 (bt, 2H), 2.36(t, 2H), 3.16 (q, 2H), 4.57 (s, 4H), 5.04 (m, 3H), 5.23 (bs, 2H), 8.17(t, 2H), 8.58 (t, 1H), 9.65 (d, 2H).

EXAMPLE 631-Pentadecylaminocarbonyloxy-3-[6-(3-thiazolio)hexyloxy]-2-methylenepropanemethanesulfonate

Following the procedure described in Example 9, but replacing1-octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropanewith1-pentadecylaminocarbonyloxy-3-[6-(methanesulfonyloxy)hexyloxy]-2-methylenepropane(from Preparation 57) the desired product was obtained.

NMR: δ=0.88 (t, 3H), 1.26 (s, 26H), 1.1-1.7 (m, 6H), 2.0 (m, 2H), 2.77(bs, 3H), 3.15 (q, 2H), 3.38 (t, 2H), 3.94 (s, 2H), 4.56 (s, 2H), 4.70(t, 2H), 5.07 (s, 1H), 5.17 (s, 2H), 8.45 (m, 2H), 10.80 (bs, 1H).

EXAMPLE 641-Pentadecylaminocarbonyloxy-3-[6-(1-pyridinio)hexyloxy]-2-methylenepropanemethanesulfonate

Following the procedure described in Example 37, but replacing1-hexadecanoyloxy-3-(8-bromooctanoyloxy)-2-methylenepropane with1-pentadecylaminocarbonyloxy-3-[6-(methanesulfonyloxy)hexyloxy]-2-methylenepropane(from Preparation 57) the desired product was obtained.

NMR: δ=0,87 (t, 3H), 1.25 (bs, 26H), 1.0-1.8 (m, 6H), 2.0 (m, 2H), 2.73(s, 3H), 3.14 (q, 2H), 3.38 (t, 2H), 3.94 (s, 2H), 4.55 (s, 2H), 4.79(t, 2H), 5.05 (bs, 1H), 5.15 (s, 2H), 8.11 (t, 2H), 8.49 (t, 1H), 9.20(d, 2H).

EXAMPLE 651-Octadecylaminocarbonyloxy-3-[6-(3-thiazolio)hexyloxy]-2-methylenepropanemethanesulfonate

Following the procedure described in Example 9, but replacing1-octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropanewith1-octadecylaminocarbonyloxy-3-[6-(methanesulfonyloxy)hexyloxy]-2-methylenepropane(from Preparation 58) the desired product was obtained.

NMR: δ=0.87 (t, 3H), 1.25 (bs, 38H), 2.0 (bm, 2H), 2.77 (s, 3H), 3.15(q, 2H), 3.38 (t, 2H), 3.95 (s, 2H), 4.57 (s, 2H), 4.70 (t, 2H), 5.10(s, 1H), 5.16 (s, 2H), 8.40 (m, 2H), 10.76 (bs, 1H).

EXAMPLE 661-Octadecylaminocarbonyloxy-3-[6-(1-pyridinio)hexyloxy]-2-methylenepropanemethanesulfonate

Following the procedure described in Example 37, but replacing1-hexadecanoyloxy-3-(8-bromooctanoyloxy)-2-methylenepropane with1-octadecylaminocarbonyloxy-3-[6-(methanesulfonyloxy)hexyloxy]-2-methylenepropane(from Preparation 58) the desired product was obtained.

NMR: δ=0.87 (t, 3H), 1.25 (s, 32H), 1.1-1.7 (m, 6H), 2.0 (m, 2H), 2.75bs, 3H), 3.15 (q, 2H), 3.38 (t, 2H), 3.94 (s, 2H), 4.56 (s, 2H), 4.80(t, 2H), 5.05 (bs, 1H), 5.16 (s, 2H), 8.08 (t, 2H), 8.45 (t, 1H), 9.22(d, 2H).

EXAMPLE 671-Octadecyloxycarbonyloxy-3-[6-(3-thiazolio)hexyloxy]-2-methylenepropanemethanesulfonate

Following the procedure described in Example 9, but replacing1-octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropanewith1-octadecyloxycarbonyloxy-3-[6-(methanesulfonyloxy)hexyloxy]-2-methylenepropane(from Preparation 56) the desired product was obtained.

NMR: δ=0.87 (s, 3H), 1.26 (s, 32H), 1.0-2.1 (m, 8H), 2.76 (bs, 3H), 3.38(t, 2H), 3.96 (s, 2H), 4.13 (t, 2H), 4.62 (s, 2H), 4.70 (t, 2H), 5.22(s, 2H), 8.35 (bs, 2H), 10.80 (s, 1H).

EXAMPLE 681-Octadecyloxycarbonyloxy-3-[6-(1-pyridinio)hexyloxy]-2-methylenepropanemethanesulfonate

Following the procedure described in Example 37, but replacing1-hexadecanoyloxy-3-(8-bromooctanoyloxy)-2-methylenepropane with1-octadecyloxycarbonyloxy-3-[6-(methanesulfonyloxy)hexyloxy]-2-methylenepropane(from Preparation 56) the desired product was obtained.

NMR: δ=0.87 (s, 3H), 1.26 (s, 32H), 1.1-2.1 (m, 8H), 2.75 (s, 3H), 3.37(t, 2H), 3.95 (s, 2H), 4.12 (t, 2H), 4.62 (s, 2H), 4.80 (t, 2H), 5.21(s, 2H), 8.10 (m, 2H), 8.50 (m, 1H), 9.31 (d, 2H).

EXAMPLE 691-Hexadecyloxycarbonyloxy-3-[6-(3-thiazolio)hexyloxy]-2-methylenepropanemethanesulfonate

Following the procedure described in Example 9, but replacing1-octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropanewith1-hexadecyloxycarbonyloxy-3-[6-(methanesulfonyloxy)hexyloxy]-2-methylenepropane(from Preparation 55), the desired product was obtained.

NMR: δ=0.88 (t, 3H), 1.26 (s, 28H), 1.1-2.0 (m, 8H), 2.77 (s, 3H), 3.39(t, 2H), 3.96 (s, 2H), 4.13 (t, 2H), 4.63 (s, 2H), 4.70 (t, 2H), 5.22(s, 2H), 8.31 (s, 2H), 10.82 (s, 1H).

EXAMPLE 701-Hexadecyloxycarbonyloxy-3-[6-(1-pyridinio)hexyloxy]-2-methylenepropanemethanesulfonate

Following the procedure described in Example 37, but replacing1-hexadecanoyloxy-3-(8-bromooctanoyloxy)-2-methylenepropane with1-hexadecyloxycarbonyloxy-3-[6-(methanesulfonyloxy)hexyloxy]-2-methylenepropane(from Preparation 55) the desired product was obtained.

NMR: δ=0.87 (t, 3H), 1.25 (s, 28H), 1.1-1.9 (m, 6H), 2.05 (m, 2H), 2.75(s, 3H), 3.37 (t, 2H), 3.95 (s, 2H), 4.12 (t, 2H), 4.62 (s, 2H), 4.82(t, 2H), 5.22 (s, 2H), 8.09 (t, 2H), 8.47 (t, 1H), 9.25 (d, 2H).

EXAMPLE 711-Octadecyloxycarbonyloxy-3-[1-(pyridinio)heptanoyloxy]-2-methylenepropanebromide

Following the procedure described in Preparation 37, but replacing1-hexadecanoyloxy-3-(8-bromooctanoyloxy)-2-methylenepropane with1-octadecyloxycarbonyloxy-3-(7-bromoheptanoyloxy)-2-methylenepropane(from Preparation 38), the desired product was obtained.

NMR: δ=0.88 (t, 3H), 1.25 (s, 32H), 1.0-1.8 (m, 6H), 2.10 (m, 2H), 2.33(t, 2H), 4.13 (t, 2H), 4.60 (s, 2H), 4.63 (s, 2H), 5.04 (t, 2H), 5.29(s, 2H), 8.15 (m, 2H), 8.55 (m, 1H), 9.57 (d, 2H).

EXAMPLE 721-Octadecylaminocarbonyloxy-3-[6-(1-quinolinio)hexanoyloxy]-2-methylenepropane bromide

Following the procedure described in Preparation 6, but replacingpyridine with quinoline, the desired product is obtained.

EXAMPLE 731-Octadecylaminocarbonyloxy-3-[6-(3-chloro-1-pyridinio)hexanoyloxy]-2-methylenepropanebromide

Following the procedure described in Preparation 9, but replacingthiazole with 3-chloropyridine, the desired product is obtained.

EXAMPLE 741-Octadecylaminocarbonyloxy-3-[7-(3-thiazolio)heptanoyloxy]-2-methylenepropane4-toluenesulfonate

1-Octadecylaminocarbonyloxy-3-[7-(3-thiazolio)heptanoyloxy]-2-methylenepropanebromide (from Example 46) (0.25 g) was dissolved in 0.1M sodium4-toluenesulfonate (50 ml) and passed through a column of Amberlite®XAD-7 (20-50 mesh, 15 ml). The column was washed with 0.1M sodium4-(toluenesulfonate (15 ml) followed by water (45 ml). Nitrogen waspassed through the column which finally was eluted with methanol (50ml). The methanol eluate was evaporated to dryness in vacuo, and thedesired product was obtained.

EXAMPLE 751-Octadecylaminocarbonyloxy-3-[7-(3-thiazolio)heptanoyloxy]-2-methylenepropanechloride

Following the procedure described in Example 74, but replacing sodium4-toluenesulfonate with sodium chloride, the desired product isobtained.

EXAMPLE 761-Octadecylaminocarbonyloxy-3-[7-(3-thiazolio)heptanoyloxy]-2-methylenepropaneiodide

Following the procedure described in Example 74, but replacing sodium4-toluenesulfonate with sodium iodide, the desired product is obtained.

EXAMPLE 77

    ______________________________________                                        Aerosol                                                                       ______________________________________                                        1-Octadecylaminocarbonyloxy-3-[7-                                                                      1,000  mg                                            (3-thiazolio)heptanoyloxy]-2-meth-                                            ylenepropane bromide (GS-1160-180)                                            (active substance)                                                            Water for injections to make                                                                           1,000  ml                                            ______________________________________                                    

The active substance is dissolved in a suitable amount of water forinjections by gentle heating. Water for injections is added to make afinal volume of 1,000 ml.

The solution is filtered through a sterile 0.2 μm membranefilter andfilled aseptically into suitable single dose containers, each containing5 ml. One dose of 5 ml (equal to 5 mg active substance) is inhaled bymeans of a suitable nebulizer.

EXAMPLE 78

    ______________________________________                                        Capsule                                                                       ______________________________________                                        GS-1160-180 (active substance)                                                                          50 g                                                Gactose fine crystalline  300 g                                               Magnesium stearate        3 g                                                 ______________________________________                                    

The active substance is mixed in a suitable mixer with lactose until ahomogeneous state is reached. The magnesium stearate is added, and theblending procedure is continued for a few minutes. By means of asuitable capsule-filling machine hard gelatine capsules size 0 arefilled, each with 353 mg of the mixture.

EXAMPLE 79

    ______________________________________                                        Tablet                                                                        ______________________________________                                        GS-1160-180             100 g                                                 (active substance)                                                            Lactose                 200 g                                                 Starch                  100 g                                                 Methylcellulose         4 g                                                   Magnesium stearate      4 g                                                   ______________________________________                                    

The active substance, lactose and starch are mixed to a homogeneousstate in a suitable mixer and moistened with a 5 percent aqueoussolution of methylcellulose 15 cps. The mixing is continued untilgranules are formed. If necessary, the wet granulation is passed througha suitable screen and dried to a water content of less than 2.5% in asuitable dryer, e.g. fluid bed or drying oven. The dried granulation ispassed through a 1 mm screen. Magnesium stearate is added, and themixing is continued for a short period of time.

Tablets with a weight of 408 mg are produced from the granulation bymeans of a suitable tabletting machine.

EXAMPLE 80

    ______________________________________                                        Suppository                                                                   ______________________________________                                        GS-1160-180              200 g                                                (active substance)                                                            Suppository base, Witepsol W-35                                                                        1,900 g                                              ______________________________________                                    

Cocoa butter is slowly heated to form a melt not exceeding 60° C. Theactive substance is added to the melt, and suppositories with a weightof 2.1 grams are prepared by moulding.

EXAMPLE 81

    ______________________________________                                        Topical formulation                                                           ______________________________________                                        I         GS-1160-180         20 g                                                      (active substance)                                                            Cetostearyl alcohol 100 g                                                     Liquid paraffin     100 g                                                     White soft paraffin 50 g                                                      Polyoxyethylene sorbitane                                                                         50 g                                                      monostearate                                                        II        Methylparaben       2 g                                                       Glycerol            100 g                                                     Water to make       1,000 g                                         ______________________________________                                    

The ingredients stated under I are melted together and heated to 70° C.in a vessel fitted with stirrer and homogenizer. In another vessel, thewater phase (II) is prepared by heating to 70° C. The water phase isslowly added to the oil phase with continuous stirring andhomogenization.

The active substance is added, and the temperature is kept for 15minutes at 70° C. The vessel is cooled to 40° C. under continuousstirring and homogenization. The cooling is continued to a temperaturebelow 25° C. under slow stirring.

EXAMPLE 82

    ______________________________________                                        Formulation for injection                                                     ______________________________________                                        GS-1160-180             10     g                                              (active substance)                                                            Ethanol                 100    g                                              Propylene glycol        200    g                                              Water for injection to make                                                                           1,000  ml                                             ______________________________________                                    

The active substance is dissolved in a mixture of ethanol and propyleneglycol by slight heating. Water for injection is added to a final volumeof 1,000 ml. The injection solution is sterile filtered through a 0.2 μmmembranefilter and filled aseptically into ampoules, each containing 5ml.

EXAMPLE 83

    ______________________________________                                        Ophthalmic solution                                                           ______________________________________                                        GS-1160-180              2 g                                                  (active substance)       50 g                                                 Mannitol                 5 g                                                  Hydroxyethylcellulose    5 g                                                  Phenyl ethyl alcohol     5 g                                                  Water for injection to make                                                                            1,000 g                                              ______________________________________                                    

A 2 percent concentrate of hydroxyethylcellulose in water for injectionincluding phenyl ethyl alcohol is prepared by slowly spreading thecellulose on the water surface. The concentrate is allowed to stand forcomplete swelling of the cellulose.

The active substance and mannitol are dissolved in the remaining amountof water of injection.

The solutions are carefully mixed together and sterilized. Under asepticconditions the solution is filled into suitable sterile containers.

What we claim is:
 1. A compound of the formula I ##STR11## where O--A¹and O--A², which can be the same or different, each represents O,O--C(O), O--C(O)NH, O--C(S)NH or O--C(O)O, R¹ represents an alkyl oralkenyl group of 10-22 carbon atoms, n is an integer from 1 to 11, B⁺represents N⁺ (Het), where --N⁺ (Het) stands for 1-pyridinio,1-pyridazinio, 1-pyrimidinio, 1-pyrazinio, 3-oxazolio, 3-thiazolio,1-isoquinolinio, 1-quinolinio, 3-alkyl-1-imid-azolio; X⁻ means the anionof a pharmaceutically acceptable inorganic or organic acid; and R² andR³ are the same or different, and represent hydrogen or alkyl groups of1-4 carbon atoms.
 2. A compound according to claim 1, in crystallineform.
 3. A compound according to claim 1, in which X⁻ stands for theanion of an inorganic acid selected from the group consisting ofhydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid,phosphoric acid, and nitric acid, or for the anion of an organic acidselected from the group consisting of acetic acid, lactic acid, tartaricacid, benzoic acid, citric acid, methanesulfonic acid, ethanesulfonicacid, benzenesulfonic acid, toluenesulfonic acid, and isethionic acid,X⁻ standing in particular for chloride, bromide, iodide, or the anionsof methanesulfonic acid or p-toluenesulfonic acid.
 4. A compoundaccording to claim 1, in which R² and R³ are both hydrogen, and n is aninteger from 4 to
 9. 5. A compound according to claim 1, selected fromthe group consisting of1-octadecylaminocarbonyloxy-3-[7-(3-thiazolio)heptanoyloxy]-2-methylenepropanebromide,1-octadecylaminocarbonyloxy-3-[6-(1-pyridinio)hexanoyloxy]-2-methylenepropanebromide,1-pentadecylaminocarbonyloxy-3-[8-(3-thiazolio)octanoyloxy]-2-methylenepropanebromide,1-hexadecyloxycarbonyloxy-3-[8-(3-thiazolio)octanoyloxy]-2-methylenepropanebromide,1-pentadecylaminocarbonyloxy-3-[8-(3-thiazolio)octanoyloxy]-2-isopropylidenepropanebromide,1-octadecylaminocarbonyloxy-3-[5-(1-pyridinio)pentylaminocarbonyloxy]-2-methylenepropanebromide,1-octadecylaminocarbonyloxy-3-[6-(3-thiazolio)hexyloxy]-2-methylenepropanemethanesulfonate.
 6. A compound according to claim 1 where --N⁺ (Het) is3-thiazolio.
 7. A compound according to claim 6 which is1-octadecylaminocarbonyloxy-3-[7-(3-thiazolio)heptanoyloxy]-2-methylenepropanebromide.
 8. A pharmaceutical composition for use in inhibiting theeffect of platelet activating factor comprising an effective amount of acompound according to claim 1, together with pharmaceuticallyacceptable, non-toxic carriers and/or auxiliary agents.
 9. Apharmaceutical composition according to claim 8, in parenteral form. 10.A pharmaceutical composition according to claim 8, in topical form. 11.A pharmaceutical composition according to claim 8, in enteral form. 12.A method for inhibiting the effect of platelet activating factor in ahost in need of such inhibiting effect which comprises administering tosaid host an effective amount of a compound according to claim 1.